tbuckley/cabot-search huggingface dataset:
Trends in life expectancy and age-specific mortality in England and Wales, 1970–2016, in comparison with a set of 22 high-income countries: an analysis of vital statistics data
Authors: David A Leon, Dmitry A Jdanov, Vladimir M Shkolnikov
Journal: The Lancet Public Health (2019)

<h2>Summary</h2><h3>Background</h3> Since 2010, the rate of improvement in life expectancy in the UK has slowed. We aimed to put this trend in the context of changes over the long term and in relation to a group of other high-income countries. <h3>Methods</h3> We compared sex-specific trends in life expectancy since 1970 and age-specific mortality in England and Wales with median values for 22 high-income countries (in western Europe, Australia, Canada, New Zealand, Japan, and the USA). We used annual mortality data (1970–2016) from the Human Mortality Database. <h3>Findings</h3> Until 2011–16, male life expectancy in England and Wales followed the median life expectancy of the comparator group. By contrast, female life expectancy was below the median and is among the lowest of the countries considered. In 2011–16, the rate of improvement in life expectancy slowed sharply for both sexes in England and Wales, and slowed more moderately in the comparator group because of negative trends in all adult age groups. This deceleration resulted in a widening gap between England and Wales and the comparators from 2011 onwards. Since the mid-2000s, for the first time, mortality rates in England and Wales among people aged 25–50 years were appreciably higher than in the comparator group. <h3>Interpretation</h3> Although many countries have seen slower increases in life expectancy since 2011, trends in England and Wales are among the worst. The poor performance of female life expectancy over the long-term is in part driven by the relative timing of the smoking epidemic across countries. The previously overlooked higher mortality among young working-age adults in England and Wales relative to other countries deserves urgent attention. <h3>Funding</h3> None.
Matrix Metalloproteinase-sensitive Multistage Nanogels Promote Drug Transport in 3D Tumor Model
Authors: Gregor Nagel, Ana Sousa-Herves, Stefanie Wedepohl, Marcelo Calderón
Journal: Theranostics (2019)

Physiological barriers inside of tumor tissue often result in poor interstitial penetration and heterogeneous intratumoral distribution of nanoparticle-based drug delivery systems (DDS). Novel, matrix metalloproteinase (MMP)-sensitive peptide-crosslinked nanogels (pNGs) as multistage DDS are reported with a beneficial size reduction property to promote the process of deep tissue penetration. Methods: The presented pNGs are based on a dendritic polyglycerol (dPG) scaffold crosslinked by a modified MMP-sensitive fluorogenic peptide. The crosslinker integrates degradability in response to proteases present in the tumor microenvironment. Surfactant-free, inverse nanoprecipitation is employed to prepare the nanogels using strain-promoted click chemistry. The size and crosslinking density of the pNGs are controlled by the functionalization degree of dPG with cyclooctyne groups and by the peptide crosslinker fraction. The intrinsic reporter moiety of the crosslinker was used to study the influence of pNG compositions on the degradation profile. The therapeutic drug Doxorubicin was conjugated through a pH-sensitive linkage to dPG to form a multistage DDS. The penetration behavior of the pNGs was studied using agarose matrix and multicellular tumor spheroids (MCTS). Results: Nanogel sizes were controlled in the range of 150-650 nm with narrow size distributions and varying degrees of crosslinking. The pNGs showed stability in PBS and cell media but were readily degraded in the presence of MMP-7. The crosslinking density influenced the degradation kinetic mediated by MMP-7 or cells. Stable conjugation of DOX at physiological pH and controlled drug release at acidic pH were observed. The digestions of nanogels lead to a size reduction to polymer-drug fragments which efficiently penetrated into agarose gels. Moreover, the degradable multistage pNGs demonstrated deeper penetration into MCTS as compared to their non-degradable counterparts. Thus, degradable pNGs were able to deliver their cargo and efficiently reduce the cell viability in MCTS. Conclusion: The triggered size reduction of the pNGs by enzymatic degradation can facilitate the infiltration of the nanocarrier into dense tissue, and thereby promote the delivery of its cargo.
The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition
Authors: Kun Zhang, Mengxia Zhang, Qingbin Yao, Xiaohui Han, Yanmian Zhao, Lina Zheng, Guantong Li, Qi Liu, Yanan Chang, Peijun Zhang, Hongmei Cui, Zhemin Shi, Ting Chen, Zhi Yao, Tao Han, Wei Hong
Journal: Theranostics (2019)

Liver fibrosis leading to cirrhosis is one of the major health burdens worldwide with currently limited therapeutic options available. Long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes in a cell- or tissue-specific manner. However, there is still an important gap in the understanding of the role of hepatocyte-specific lncRNAs in liver fibrosis. Methods: The expressions of lnc-Hser in human and mice fibrotic livers as well as primary hepatocytes (HCs) of mice developing liver fibrosis were determined by real-time RT-PCR. The roles and mechanisms of lnc-Hser in HCs and liver fibrosis were determined in vitro and in vivo. Results: In this study, we have identified a hepatocyte-specifically expressed lnc-Hser, which was reduced in human and mice fibrotic livers as well as primary HCs of mice developing liver fibrosis. We have shown that silencing lnc-Hser aggravated liver fibrosis both in vitro and in vivo through inducing the epithelial-mesenchymal transition (EMT) and the apoptosis of HCs. In addition, knockdown of lnc-Hser promoted hepatic stellate cells (HSCs) activation through the signals derived from injured HCs. Mechanistically, we have revealed that lnc-Hser inhibited HCs apoptosis via the C5AR1-Hippo-YAP pathway and suppressed HCs EMT via the Notch signaling. Conclusions: Our work has identified a hepatocyte-specific lnc-HSER that regulates liver fibrosis, providing a proof that this molecule is a novel biomarker for damaged HCs and a potential target for anti-fibrotic therapy.
Metastatic Nasopharyngeal Carcinoma Treated With Intraarterial Combined With Intravenous Peptide Receptor Radionuclide Therapy
Authors: Wenjia Zhu, Jingjing Zhang, Aviral Singh, Harshad R. Kulkarni, Richard P. Baum
Journal: Clinical Nuclear Medicine (2019)

Abstract Nasopharyngeal carcinoma may express somatostatin receptors (SSTR). We present a case with metastatic nasopharyngeal carcinoma in the liver, bone, and lymph nodes. The patient was in progression after chemotherapy, external beam radiation therapy (ERBT), atezolizumab, and cetuximab. Due to strong SSTR expression of the metastases, PRRT was applied. After 3 cycles of intravenous 177 Lu-DOTATOC and 1 cycle of intraarterial 90 Y-DOTATOC therapy, the hepatic and bone metastases showed excellent response after PRRT. No nephrotoxicity or myelotoxicity was observed.
Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload–Driven Heart Failure Reveals Extent of Immune Activation
Authors: Elisa Martini, Paolo Kunderfranco, Clelia Peano, Pierluigi Carullo, Marco Cremonesi, Tilo Schorn, Roberta Carriero, Alberto Termanini, Federico Simone Colombo, Elena Jachetti, Cristina Panico, Giuseppe Faggian, Andrea Fumero, Lucia Torracca, Martina Molgora, Javier Cibella, Christina Pagiatakis, Jolanda Brummelman, Giorgia Alvisi, Emilia Maria Cristina Mazza, Mario Paolo Colombo, Enrico Lugli, Gianluigi Condorelli, Marinos Kallikourdis
Journal: Circulation (2019)

Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure. Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response.Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45+ cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multiparameter flow cytometry, immunohistochemistry, and tissue clarification immunofluorescence in mouse and human.We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells, dendritic cells, Natural Killer cells, neutrophils, and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whereas mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as oncostatin M in proinflammatory macrophages and PD-1 in regulatory T cells, that may help explain clinical findings such as the refractivity of patients with heart failure to anti-tumor necrosis factor therapy and cardiac toxicity during anti-PD-1 cancer immunotherapy, respectively.Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, Natural Killer cells, and mast cells. This opens up the field of cardioimmunology to further investigation by using toolkits that have already been developed to study the aforementioned immune subsets. The subset-specific molecules that mediate their activation may thus become useful targets for the diagnostics or therapy of heart failure.
Prenatal Exposure to PM2.5 and Cardiac Vagal Tone during Infancy: Findings from a Multiethnic Birth Cohort
Authors: Whitney J. Cowell, Kelly J. Brunst, Ashley J. Malin, Brent A. Coull, Chris Gennings, Itai Kloog, Lianna Lipton, Robert O. Wright, Michelle Bosquet Enlow, Rosalind J. Wright
Journal: Environmental Health Perspectives (2019)

BACKGROUND: The autonomic nervous system plays a key role in maintaining homeostasis and responding to external stimuli.In adults, exposure to fine particulate matter (PM 2:5 ) has been associated with reduced heart rate variability (HRV), an indicator of cardiac autonomic control.OBJECTIVES: Our goal was to investigate the associations of exposure to fine particulate matter (PM 2:5 ) with HRV as an indicator of cardiac autonomic control during early development.METHODS: We studied 237 maternal-infant pairs in a Boston-based birth cohort.We estimated daily residential PM 2:5 using satellite data in combination with land-use regression predictors.In infants at 6 months of age, we measured parasympathetic nervous system (PNS) activity using continuous electrocardiogram monitoring during the Repeated Still-Face Paradigm, an experimental protocol designed to elicit autonomic reactivity in response to maternal interaction and disengagement.We used multivariable linear regression to examine average PM 2:5 exposure across pregnancy in relation to PNS withdrawal and activation, indexed by changes in respiration-corrected respiratory sinus arrhythmia (RSA c )-an established metric of HRV that reflects cardiac vagal tone.We examined interactions with infant sex using cross-product terms.RESULTS: In adjusted models we found that a 1-unit increase in PM 2:5 (in micrograms per cubic meter) was associated with a 3.53% decrease in baseline RSA c (95% CI: -6:96, 0.02).In models examining RSA c change between episodes, higher PM 2:5 was generally associated with reduced PNS withdrawal during stress and reduced PNS activation during recovery; however, these associations were not statistically significant.We did not observe a significant interaction between PM 2:5 and sex.
Experience abroad and participation in ESCMID educational activities: results from a survey among French infectious diseases specialists in training
Authors: G. Catho, N. Peiffer-Smadja, J. Gras, L. Osei, M. Le Maréchal, Simon Bessis, Alexandre Bleibtreu, Kevin Bouiller, Mathieu Cabon, Vincent Dubee, Maxime Hentzien, Adrien Lemaignen, Michael Thy, Capucine Martins, Pauline Thill
Journal: Clinical Microbiology and Infection (2019)
Recent advances and challenges of repurposing nanoparticle-based drug delivery systems to enhance cancer immunotherapy
Authors: Seungho Lim, Jooho Park, Man Kyu Shim, Wooram Um, Hong Yeol Yoon, Ju Hee Ryu, Dong-Kwon Lim, Kwangmeyung Kim
Journal: Theranostics (2019)

Cancer immunotherapy is an attractive treatment option under clinical settings.However, the major challenges of immunotherapy include limited patient response, limited tumor specificity, immune-related adverse events, and immunosuppressive tumor microenvironment.Therefore, nanoparticle (NP)-based drug delivery has been used to not only increase the efficacy of immunotherapeutic agents, but it also significantly reduces the toxicity.In particular, NP-based drug delivery systems alter the pharmacokinetic (PK) profile of encapsulated or conjugated immunotherapeutic agents to targeted cancer cells or immune cells and facilitate the delivery of multiple therapeutic combinations to targeted cells using single NPs.Recently, advanced NP-based drug delivery systems were effectively utilized in cancer immunotherapy to reduce the toxic side effects and immune-related adverse events.Repurposing these NPs as delivery systems of immunotherapeutic agents may overcome the limitations of current cancer immunotherapy.In this review, we focus on recent advances in NP-based immunotherapeutic delivery systems, such as immunogenic cell death (ICD)-inducing drugs, cytokines and adjuvants for promising cancer immunotherapy.Finally, we discuss the challenges facing current NP-based drug delivery systems that need to be addressed for successful clinical application.
Anaplastic Lymphoma Kinase Gene Rearrangement in Children and Young Adults With Mesothelioma
Authors: Idrees Mian, Zied Abdullaev, Betsy Morrow, Rosandra N. Kaplan, Shaojian Gao, Markku Miettinen, David S. Schrump, Valerie Zgonc, Jun S. Wei, Javed Khan, Svetlana Pack, Raffit Hassan
Journal: Journal of Thoracic Oncology (2019)
FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice
Authors: Liang Kuang, Jiangyi Wu, Nan Su, Huabing Qi, Hangang Chen, Siru Zhou, Yan Xiong, Xiaolan Du, Qiaoyan Tan, Jing Yang, Min Jin, Fengtao Luo, Junjie Ouyang, Bin Zhang, Zuqiang Wang, Wanling Jiang, Liang Chen, Shuai Chen, Ziming Wang, Peng Liu, Liangjun Yin, Fengjin Guo, Chuxia Deng, Di Chen, Chuanju Liu, Yangli Xie, Zhenhong Ni, Lin Chen
Journal: Annals of the Rheumatic Diseases (2019)

This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis.Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis.R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice.Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.
Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues
Authors: Courtney W. Hanna, Raquel Pérez-Palacios, Lenka Gahurova, Michael Schubert, Felix Krueger, Laura Biggins, Simon Andrews, Maria Colomé-Tatché, Deborah Bourc’his, Wendy Dean, Gavin Kelsey
Journal: Genome biology (2019)

Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages, and uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored.We identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression, and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation-dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associated with non-canonical imprints is not maintained beyond pre-implantation development at these elements and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in the epiblast.This study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development and identifies an integral role for ERVK LTR repetitive elements.
Palliative treatment of chronic breathlessness syndrome: the need for P5 medicine
Authors: Daisy J A Janssen, Miriam J Johnson
Journal: Thorax (2019)

After a CNS injury in the adult mammals, axonal regeneration is very limited because of the reduced intrinsic growth capacity and nonpermissive environment for axonal elongation. The growth inhibitions from CNS myelin and astroglial chondroitin sulfate proteoglycans partially account for the lack of CNS repair. Here, we show that the nonsteroidal antiinflammatory drugs (NSAIDs) ibuprofen and indomethacin, the drugs widely used as pain relievers in the clinic, can surmount axon growth restrictions from myelin and proteoglycans by potently inhibiting their downstream pathway RhoA signal. Similar to Rho and Rock inhibitors C3 transferase or Y27632 [(<i>R</i>)-(+)-<i>trans-N</i>-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], both NSAID drugs stimulate a significant neurite growth in the cultured dorsal root ganglion neurons exposed to the inhibitory substrates. Systemic administration of ibuprofen to spinal cord-lesioned rodents reverses the active RhoA signal around injury area measured via Rho-GTP binding assay. Subcutaneous injections of ibuprofen via minipumps to rats with a thoracic spinal cord transection or contusion injury result in substantial corticospinal and serotonergic axon sprouting in the caudal spinal cord and promote locomotor functional recovery, even delaying the treatment 1 week after trauma. In contrast, the non-RhoA-inhibiting NSAID naproxen does not have the axon growth-promoting effects on cultured or lesioned neurons. These studies demonstrate the therapeutic potential of RhoA-inhibiting NSAIDs in treating CNS injuries characterized by axonal disconnection including spinal cord injury.
Effects of maternal iron status on placental and fetal iron homeostasis
Authors: Veena Sangkhae, Allison L. Fisher, Shirley Wong, Mary Dawn Koenig, Lisa Tussing-Humphreys, Alison Chu, Melisa Lelić, Tomas Ganz, Elizabeta Nemeth
Journal: Journal of Clinical Investigation (2019)

Iron deficiency is common worldwide and is associated with adverse pregnancy outcomes. The increasing prevalence of indiscriminate iron supplementation during pregnancy also raises concerns about the potential adverse effects of iron excess. We examined how maternal iron status affects the delivery of iron to the placenta and fetus. Using mouse models, we documented maternal homeostatic mechanisms that protect the placenta and fetus from maternal iron excess. We determined that under physiological conditions or in iron deficiency, fetal and placental hepcidin did not regulate fetal iron endowment. With maternal iron deficiency, critical transporters mediating placental iron uptake (transferrin receptor 1 [TFR1]) and export (ferroportin [FPN]) were strongly regulated. In mice, not only was TFR1 increased, but FPN was surprisingly decreased to preserve placental iron in the face of fetal iron deficiency. In human placentas from pregnancies with mild iron deficiency, TFR1 was increased, but there was no change in FPN. However, induction of more severe iron deficiency in human trophoblast in vitro resulted in the regulation of both TFR1 and FPN, similar to what was observed in the mouse model. This placental adaptation that prioritizes placental iron is mediated by iron regulatory protein 1 (IRP1) and is important for the maintenance of mitochondrial respiration, thus ultimately protecting the fetus from the potentially dire consequences of generalized placental dysfunction.