tbuckley/cabot-search huggingface dataset:
Disruption of <i>mosGILT</i> in <i>Anopheles gambiae</i> impairs ovarian development and <i>Plasmodium</i> infection
Authors: Jing Yang, Tyler R. Schleicher, Yuemei Dong, Hyun Bong Park, Jiangfeng Lan, Peter Cresswell, Jason Crawford, George Dimopoulos, Erol Fikrig
Journal: The Journal of Experimental Medicine (2019)

Plasmodium infection in Anopheles is influenced by mosquito-derived factors. We previously showed that a protein in saliva from infected Anopheles, mosquito gamma-interferon–inducible lysosomal thiol reductase (mosGILT), inhibits the ability of sporozoites to traverse cells and readily establish infection of the vertebrate host. To determine whether mosGILT influences Plasmodium within the mosquito, we generated Anopheles gambiae mosquitoes carrying mosaic mutations in the mosGILT gene using CRISPR/CRISPR associated protein 9 (Cas9). Here, we show that female mosaic mosGILT mutant mosquitoes display defects in ovarian development and refractoriness to Plasmodium. Following infection by either Plasmodium berghei or Plasmodium falciparum, mutant mosquitoes have significantly reduced oocyst numbers as a result of increased thioester-containing protein 1 (TEP1)–dependent parasite killing. Expression of vitellogenin (Vg), the major yolk protein that can reduce the parasite-killing efficiency of TEP1, is severely impaired in mutant mosquitoes. MosGILT is a mosquito factor that is essential for ovarian development and indirectly protects both human and rodent Plasmodium species from mosquito immunity.
Hepatitis C Virus NAT‐Positive Solid Organ Allografts Transplanted Into Hepatitis C Virus–Negative Recipients: A Real‐World Experience
Authors: Nikhil Kapila, K.V. Narayanan Menon, Kawtar Al‐Khalloufi, Jason M. Vanatta, Carla Murgas, Diego Reino, Samer Ebaid, Joshua J. Shaw, Neerja Agrawal, Salwa Rhazouani, Viviana Navas, Cedric Sheffield, Asad Ur Rahman, Michael Castillo, Christina C. Lindenmeyer, Charles Miller, Cristiano Quintini, Xaralambos B. Zervos
Journal: Hepatology (2019)

Background and Aims Hepatitis C virus (HCV)‐viremic organs are underutilized, and there is limited real‐world experience on the transplantation of HCV‐viremic solid organs into recipients who are HCV negative. Approach and Results Patients listed or being evaluated for solid organ transplant after January 26, 2018, were educated and consented by protocol on the transplantation of HCV‐viremic organs. All recipients were HCV nucleic acid test and anti‐HCV antibody negative at the time of transplant and received an HCV‐viremic organ. The primary outcome was sustained virological response (SVR) at 12 weeks after completion of direct‐acting antiviral (DAA) therapy (SVR 12 ). Seventy‐seven patients who were HCV negative underwent solid organ transplantation from a donor who was HCV viremic. No patients had evidence of advanced hepatic fibrosis. Treatment regimen and duration were at the discretion of the hepatologist. Sixty‐four patients underwent kidney transplant (KT), and 58 KT recipients had either started or completed DAA therapy. Forty‐one achieved SVR 12 , 10 had undetectable viral loads but are not eligible for SVR 12 , and 7 remain on treatment. One KT recipient was a nonresponder because of nonstructural protein 5A resistance. Four patients underwent liver transplant and 2 underwent liver‐kidney transplant. Three patients achieved SVR 12 , 1 has completed DAA therapy, and 2 remain on treatment. Six patients underwent heart transplant and 1 underwent heart‐kidney transplant. Six patients achieved SVR 12 and 1 patient remains on treatment. Conclusions Limited data exist on the transplantation of HCV‐viremic organs into recipients who are HCV negative. Our study is the largest to describe a real‐world experience of the transplantation of HCV‐viremic organs into recipients who are aviremic. In carefully selected patients, the use of HCV‐viremic grafts in the DAA era appears to be efficacious and well tolerated.
PLGA Porous Microspheres Dry Powders for Codelivery of Afatinib‐Loaded Solid Lipid Nanoparticles and Paclitaxel: Novel Therapy for EGFR Tyrosine Kinase Inhibitors Resistant Nonsmall Cell Lung Cancer
Authors: Yao Yang, Zhengwei Huang, Jinyuan Li, Ziran Mo, Ying Huang, Cheng Ma, Wenhao Wang, Xin Pan, Chuanbin Wu
Journal: Advanced Healthcare Materials (2019)

Abstract Combination therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR TKIs) with other chemotherapeutic agents is a feasible strategy to overcome resistance that often occurs after 9–13 months of EGFR TKIs administration in nonsmall cell lung cancer (NSCLC). In this study, a pulmonary microspheres system that codelivers afatinib and paclitaxel (PTX) is developed for treatment of EGFR TKIs resistant NSCLC. In this system, afatinib is loaded in stearic acid‐based solid lipid nanoparticles, then these nanoparticles and PTX are loaded in poly‐lactide‐ co ‐glycolide‐based porous microspheres. These inhaled microspheres systems are characterized including geometric particle size, drug encapsulation efficiency, morphology by scanning electron microscopy, specific surface area, in vitro drug release, and aerodynamic particle size. Cell experiments indicate that afatinib and PTX have a synergistic effect and the codelivery system shows a superior treatment effect in drug‐resistant NSCLC cells. The biocompatibility, pharmacokinetic, and tissue distribution experiments in Sprague–Dawley rats show that afatinib and PTX in the system can maintain 96 h of high lung concentration but low concentration in other tissues, with acceptable safety. These results demonstrate that this system may be a prospective delivery strategy for drug combination treatment in cancers developing resistance, especially drug‐resistant lung cancer.
Biotin interference in high-sensitivity cardiac troponin T testing: a real-world evaluation in acute cardiac care
Authors: Wim H M Vroemen, William P T M van Doorn, Dorien M Kimenai, Will K W H Wodzig, Douwe de Boer, Otto Bekers, Steven J R Meex
Journal: Cardiovascular Research (2019)

Figure 1 Bland-Altman plot of absolute hs-cTnT concentration differences before and after biotin depletion in 572 patients.The open dots are individual data points.The black line represents the median difference (0.00, 95% CI: -0.02 to 0.00) and the grey line is the reference line.
Violence in England and Wales: does media reporting match the data?
Authors: David K Humphreys, Michelle Degli Esposti, Frances Gardner, Jonathan Shepherd
Journal: BMJ (2019)

Data sources on serious violenceSupplementary Table 1 summarises the three data sources we used to estimate trends in serious violence in England and Wales from 2002 to 2018.We manually extracted the count data from annual reports for Mortality Statistics and Hospital Episode Statistics (HES), 1,2 and derived rates per 1000 population using the Office for National Statistics' Mid-Year Population Estimates for England and Wales. 3Rates per 1000 population were already estimated for Attendances to Emergency Departments by the National Violence Surveillance Network (at Cardiff University).We extracted these estimated rates from the National Violence Surveillance Network's annual reports. 4The data and code for replicating the graphs included in the manuscript and are freely available at Github (https://github.com/DKHumphreys). 1, Mortality Statistics use ICD codes based on information from medical certificates.Contrary to police-recorded homicides which uses a subtractive approach, the data generation process for mortality statistics uses an additive approach, where deaths by homicides are added following coroner inquests.This means that homicide figures (ICD codes: X85-Y09, including late effects of assault Y87.1) for more recent years may underestimate the true number of homicides while inquests and investigations are still pending. Mortality Statistics. As described in Supplementary TableDifferent approaches may be used to counteract this limitation (see Supplementary Figure 1).Specifically, ICD codes for accelerated registrations of probable homicide pending verdict may be included (special purpose ICD code: Y33.9/U50.9)and/or deaths the broader category of death by undetermined intent (ICD codes: Y10-Y34).Including these ICD codes shift the bias in the opposite direction, overestimating recent homicide counts as a proportion of these cases will not be determined to be homicide following investigations.Although there are no specific ICD codes for homicide by knife pending verdict, there is a specific ICD code for death by knife of undetermined intent (ICD: Y28), but this code may include suicide and accidental deaths by knife (see Supplementary Figure 2).In the main manuscript, we report a combined homicide figure for homicide (ICD codes: X85-Y09), late effects of assault (ICD code: 87.1), and probable homicide pending investigation (special purpose ICD code:
Pediatric Trials for Cancer Therapies With Targets Potentially Relevant to Pediatric Cancers
Authors: Thomas J Hwang, Liat Orenstein, Steven G DuBois, Katherine A Janeway, Florence T Bourgeois
Journal: JNCI Journal of the National Cancer Institute (2019)

The Research to Accelerate Cures and Equity (RACE) for Children Act was enacted in 2017 to authorize the US Food and Drug Administration (FDA) to require pediatric studies for new cancer drugs that have a molecular target relevant to the growth or progression of a pediatric cancer. To assess the possible scope of this new policy, we examined all 78 adult cancer drugs approved by the FDA from 2007 to 2017. Only 17 (21.8%) drugs received any pediatric labeling information. Based on the FDA's Pediatric Molecular Target List, we found that the RACE Act could have increased the proportion of cancer drugs potentially subject to pediatric study requirements from 0% to 78.2%. However, the actual effect of the legislation will depend on how often regulators require pediatric trials and on timely completion of such trials.
Screening migrants for tuberculosis and latent TB infection: the reward will come later
Authors: Jean-Pierre Zellweger
Journal: European Respiratory Journal (2019)

In the majority of industrialised countries, migrants represent a large proportion of all cases of tuberculosis (TB) notified and the prospect of TB elimination, even in low-incidence countries, is largely dependent of the possibility of controlling TB in migrants. Most countries have therefore implemented procedures for screening migrants who may be carriers of active TB or, more rarely, for the detection and preventive treatment of latent tuberculosis infection (LTBI). The ideas behind these procedures are to protect the local population from the import of a potential transmissible disease and to prevent the emergence of TB months or years after entry into the country of settlement. Screening migrants for TB may contribute to the global decrease expected by the End TB Strategy <http://bit.ly/2kdVAtE>
Mcl-1 Interacts with Akt to Promote Lung Cancer Progression
Authors: Guo Chen, Dongkyoo Park, Andrew T. Magis, Madhusmita Behera, Suresh S. Ramalingam, Taofeek K. Owonikoko, Gabriel L. Sica, Keqiang Ye, Chao Zhang, Zhengjia Chen, Walter J. Curran, Xingming Deng
Journal: Cancer Research (2019)

Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth. Depletion of endogenous Mcl-1 from human lung cancer cells using CRISPR/Cas9 or Mcl-1 shRNA significantly decreased Akt activity, leading to suppression of lung cancer cell growth in vitro and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in tumor tissues from patients with non-small cell lung cancer. Using the Mcl-1-binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer in vitro and in vivo. By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of lung cancer. SIGNIFICANCE: These findings indicate that targeting Mcl-1/Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for cancer treatment.
Data Integration for Large-Scale Models of Species Distributions
Authors: Nick J.B. Isaac, Marta A. Jarzyna, Petr Keil, Lea I. Dambly, Philipp H. Boersch-Supan, Ella Browning, Stephen N. Freeman, Nick Golding, Gurutzeta Guillera-Arroita, Peter A. Henrys, Susan Jarvis, José Lahoz-Monfort, Jörn Pagel, Oliver L. Pescott, Reto Schmucki, Emily G. Simmonds, Robert B. O’Hara
Journal: Trends in Ecology & Evolution (2019)

With the expansion in the quantity and types of biodiversity data being collected, there is a need to find ways to combine these different sources to provide cohesive summaries of species' potential and realized distributions in space and time. Recently, model-based data integration has emerged as a means to achieve this by combining datasets in ways that retain the strengths of each. We describe a flexible approach to data integration using point process models, which provide a convenient way to translate across ecological currencies. We highlight recent examples of large-scale ecological models based on data integration and outline the conceptual and technical challenges and opportunities that arise.
On-demand storage and release of antimicrobial peptides using Pandora's box-like nanotubes gated with a bacterial infection-responsive polymer
Authors: Junjian Chen, Xuetao Shi, Ye Zhu, Yunhua Chen, Meng Gao, Huichang Gao, Lei Liu, Lin Wang, Chuanbin Mao, Yingjun Wang
Journal: Theranostics (2019)

Background: Localized delivery of antimicrobial agents such as antimicrobial peptides (AMPs) by a biomaterial should be on-demand.Namely, AMPs should be latent and biocompatible in the absence of bacterial infection, but released in an amount enough to kill bacteria immediately in response to bacterial infection.Methods: To achieve the unmet goal of such on-demand delivery, here we turned a titanium implant with titania nanotubes (Ti-NTs) into a Pandora's box.The box was loaded with AMPs (HHC36 peptides, with a sequence of KRWWKWWRR) inside the nanotubes and "closed" (surface-modified) with a pH-responsive molecular gate, poly(methacrylic acid) (PMAA), which swelled under normal physiological conditions (pH 7.4) but collapsed under bacterial infection (pH ≤ 6.0).Thus, the PMAA-gated Ti-NTs behaved just like a Pandora's box.The box retarded the burst release of AMPs under physiological conditions because the gate swelled to block the nanotubes opening.However, it was opened to release AMPs to kill bacteria immediately when bacterial infection occurred to lowering the pH (and thus made the gate collapse).Results: We demonstrated such smart excellent bactericidal activity against a panel of four clinically important bacteria, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus.In addition, this box was biocompatible and could promote the osteogenic differentiation of human mesenchymal stem cells.Both in vitro and in vivo studies confirmed the smart "on-demand" bactericidal activity of the Pandora's box.The molecularly gated Pandora's box design represents a new strategy in smart drug delivery.
Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme‐Directed Assembly
Authors: Claudia Battistella, Cassandra E. Callmann, Matthew P. Thompson, Shiyin Yao, Anjana V. Yeldandi, Tomoko Hayashi, Dennis A. Carson, Nathan C. Gianneschi
Journal: Advanced Healthcare Materials (2019)

Abstract Amphiphilic diblock copolymers are prepared by ring opening metathesis polymerization, with one block containing hydrophobic Toll‐like receptor 7 (TLR7) agonists and one block containing hydrophilic peptides as substrates for matrix metalloproteinases (MMPs). A fluorescent label is incorporated into the polymer chains for in vivo imaging. Upon dialysis against aqueous solution, polymers form 15 nm spherical micelles. Subsequent exposure to MMP‐9 elicits a morphological change to yield immunostimulatory microscale assemblies. The intravenous (IV) administration of the formulation to mice bearing 4T1 breast cancer tumors results in nanoparticle accumulation in tumors, reduction in primary tumor growth, and inhibition of lung metastases, as compared to saline‐treated animals. Mice administered the parent immunotherapeutic small molecule (1V209) experience significantly increased plasma levels of proinflammatory cytokines IL‐6, IP‐10, and MCP‐1 at 2 h following IV administration, whereas the nanomaterial shows no increase over saline‐treated controls. These data suggest that covalently packaging low molecular weight immunotherapeutics at high weight percent loadings in enzyme‐responsive nanoparticles maintains drug efficacy while decreasing immunotoxicity, providing a platform for cancer immunotherapeutic delivery.
Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation
Authors: Yanjun Li, Vivi Kasim, Xuesong Yan, Lang Li, Ian Timothy Sembiring Meliala, Can Huang, Zhuolin Li, Ke Lei, Guanbin Song, Xiaodong Zheng, Shourong Wu
Journal: Theranostics (2019)

Lipid accumulation is a driving force in tumor development, as it provides tumor cells with both energy and the building blocks of phospholipids for construction of cell membranes. Aberrant homeostasis of lipid metabolism has been observed in various tumors; however, the molecular mechanism has not been fully elucidated. Methods: Yin yang 1 (YY1) expression in hepatocellular carcinoma (HCC) was analyzed using clinical specimens, and its roles in HCC in lipid metabolism were examined using gain- and loss-of function experiments. The mechanism of YY1 regulation on peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and its downstream genes medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were investigated using molecular biology and biochemical methods. The role of YY1/ PGC-1β axis in hepatocarcinogenesis was studied using xenograft experiment. Results: This study showed that YY1 suppresses fatty acid β-oxidation, leading to increase of cellular triglyceride level and lipid accumulation in HCC cells, and subsequently induction of the tumorigenesis potential of HCC cells. Molecular mechanistic study revealed that YY1 blocks the expression of PGC-1β, an activator of fatty acid β-oxidation, by directly binding to its promoter; and thus downregulates PGC-1β/MCAD and PGC1-β/LCAD axis. Importantly, we revealed that YY1 inhibition on PGC-1β occurs irrespective of the expression of hypoxia-inducible factor-1α (HIF1-α), enabling it to promote lipid accumulation under both normoxic and hypoxic conditions. Conclusion: Our study reveals the critical role of YY1/PGC-1β axis in HCC cell lipid metabolism, providing novel insight into the molecular mechanisms associated with tumor cell lipid metabolism, and a new perspective regarding the function of YY1 in tumor progression. Thus, our study provides evidences regarding the potential of YY1 as a target for lipid metabolism-based anti-tumor therapy.
Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment
Authors: Zhi-Xuan Li, Zi-Qi Zheng, Zhuo-Hui Wei, Lu-Lu Zhang, Feng Li, Li Lin, Rui-Qi Liu, Xiao-Dan Huang, Jia-Wei Lv, Fo-Ping Chen, Xiao-Jun He, Jia-Li Guan, Jia Kou, Jun Ma, Guan-Qun Zhou, Ying Sun
Journal: Theranostics (2019)

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.