tbuckley/cabot-search huggingface dataset:
Membrane TLR9 Positive Neutrophil Mediated MPLA Protects Against Fatal Bacterial Sepsis
Authors: Zhaogang Yang, Luowei Wang, Hongmei Yu, Ruonan Wang, Yawei Gou, MingMing Zhang, Chen Kang, Tongzheng Liu, Yu Lan, Xiaobing Wang, Jiwei Liu, Merideth A. Cooper, Xin Li, Kai Yue, Yongli Yu, Liying Wang, Betty Y.S. Kim, Wen Jiang, Wei Sun
Journal: Theranostics (2019)

Sepsis is a major cause of patient mortality and morbidity from bacterial infections.Although neutrophils are known to be important in the development of sepsis, how distinctive neutrophil subtypes regulate inflammatory processes involved in septicemia remains unclear.Preconditioning protects organisms against subsequent higher-dose exposures to the same, or even different, stimuli.Several studies have reported various effects of preconditioning on immune cells.However, the detailed mechanisms underlying neutrophil-mediated protection through preconditioning in sepsis remain unknown.Methods: Flow cytometry was conducted to sort the mice peritoneal lavage cells and the blood samples from patients with sepsis.Western blotting and ELISA were carried out to elucidate the expression of TLR9 signal transduction pathway proteins.Histological analysis was used to assess the effect of InP on intestine and liver structure in tlr9 -/ -and cav-1 -/ -mice.Fluorescence microscopy, Co-IP, and FRET were carried out to determine the association of TLR9 with Cav-1.Results: We show that membrane toll-like receptor-9 positive (mTLR9 + ) neutrophils exert a protective effect against fatal bacterial infections through the process of inflammatory preconditioning (InP).InP, which occurs in the setting of a low-dose bacterial challenge, active ingredient is Monophosphoryl lipid A (MPLA), triggers the membrane translocation of TLR9 from the neutrophil cytosol, where it binds to Cav-1.Our findings showed that InP enables TLR9 to facilitate MyD88-mediated TRAF3 and IRF3 signal transduction.Depletion of either TLR9 or Cav-1 largely eliminates the neutrophil-mediated InP effect in sepsis models in vitro and in vivo.Further, examination of clinical samples from patients with sepsis showed that clinical outcomes and likelihood of recovery are closely correlated with mTLR9 and Cav-1 expression in circulating neutrophils. Conclusion:These results demonstrate that the TLR9-Cav-1 axis is a critical signaling pathway involved in the regulation of neutrophil-dependent MPLA mediated InP, and the presence of mTLR9 + neutrophils could be an attractive indicator of clinical outcomes in bacterial sepsis that could be further explored as a potential therapeutic target.
Caught in the Web — U.S. Immigration and Compound Disadvantage
Authors: Zackary D. Berger, Daniel S. Goldberg
Journal: New England Journal of Medicine (2019)

Faced with gastroesophageal reflux disease, a behavioral health disorder, and difficulty navigating the U.S. health care system, a Honduran immigrant stops working and takes up a collection to return home. His compound disadvantage has profound ethical implications.
Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy
Authors: Anne Louise Oaklander, Maria Nolano
Journal: JAMA Neurology (2019)

Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)-immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity. A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations. Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress. Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered.Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes. The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.
Comparative Validation of Breast Cancer Risk Prediction Models and Projections for Future Risk Stratification
Authors: Parichoy Pal Choudhury, Amber N Wilcox, Mark N Brook, Yan Zhang, Thomas Ahearn, Nick Orr, Penny Coulson, Minouk J Schoemaker, Michael E Jones, Mitchell H Gail, Anthony J Swerdlow, Nilanjan Chatterjee, Montserrat Garcia-Closas
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background External validation of risk models is critical for risk-stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) as a flexible tool for risk model development and comparative model validation and to make projections for population risk stratification. Methods Performance of two recently developed models, one based on the Breast and Prostate Cancer Cohort Consortium analysis (iCARE-BPC3) and another based on a literature review (iCARE-Lit), were compared with two established models (Breast Cancer Risk Assessment Tool and International Breast Cancer Intervention Study Model) based on classical risk factors in a UK-based cohort of 64 874 white non-Hispanic women (863 patients) age 35–74 years. Risk projections in a target population of US white non-Hispanic women age 50–70 years assessed potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS). Results The best calibrated models were iCARE-Lit (expected to observed number of cases [E/O] = 0.98, 95% confidence interval [CI] = 0.87 to 1.11) for women younger than 50 years, and iCARE-BPC3 (E/O = 1.00, 95% CI = 0.93 to 1.09) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify approximately 500 000 women at moderate to high risk (&amp;gt;3% 5-year risk) in the target population. Addition of MD and a 313-variant PRS is expected to increase this number to approximately 3.5 million women, and among them, approximately 153 000 are expected to develop invasive breast cancer within 5 years. Conclusions iCARE models based on classical risk factors perform similarly to or better than BCRAT or IBIS in white non-Hispanic women. Addition of MD and PRS can lead to substantial improvements in risk stratification. However, these integrated models require independent prospective validation before broad clinical applications.
Hepatocyte Stress Increases Expression of Yes‐Associated Protein and Transcriptional Coactivator With PDZ‐Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis
Authors: Meghan Mooring, Brendan H. Fowl, Shelly Z.C. Lum, Ye Liu, Kangning Yao, Samir Softic, Rory Kirchner, Aaron Bernstein, Aatur D. Singhi, Daniel G. Jay, C. Ronald Kahn, Fernando D. Camargo, Dean Yimlamai
Journal: Hepatology (2019)

Background and Aims Activated hepatocytes are hypothesized to be a major source of signals that drive cirrhosis, but the biochemical pathways that convert hepatocytes into such a state are unclear. We examined the role of the Hippo pathway transcriptional coactivators Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ) in hepatocytes to facilitate cell–cell interactions that stimulate liver inflammation and fibrosis. Approach and Results Using a variety of genetic, metabolic, and liver injury models in mice, we manipulated Hippo signaling in hepatocytes and examined its effects in nonparenchymal cells to promote liver inflammation and fibrosis. YAP‐expressing hepatocytes rapidly and potently activate the expression of proteins that promote fibrosis (collagen type I alpha 1 chain, tissue inhibitor of metalloproteinase 1, platelet‐derived growth factor c, transforming growth factor β2) and inflammation (tumor necrosis factor, interleukin 1β). They stimulate expansion of myofibroblasts and immune cells, followed by aggressive liver fibrosis. In contrast, hepatocyte‐specific YAP and YAP/TAZ knockouts exhibit limited myofibroblast expansion, less inflammation, and decreased fibrosis after CCl 4 injury despite a similar degree of necrosis as controls. We identified cellular communication network factor 1 (CYR61) as a chemokine that is up‐regulated by hepatocytes during liver injury but is expressed at significantly lower levels in mice with hepatocyte‐specific deletion of YAP or TAZ. Gain‐of‐function and loss‐of‐function experiments with CYR61 in vivo point to it being a key chemokine controlling liver fibrosis and inflammation in the context of YAP/TAZ. There is a direct correlation between levels of YAP/TAZ and CYR61 in liver tissues of patients with high‐grade nonalcoholic steatohepatitis. Conclusions Liver injury in mice and humans increases levels of YAP/TAZ/CYR61 in hepatocytes, thus attracting macrophages to the liver to promote inflammation and fibrosis.
Genetic polymorphisms, toxicity, and response rate in African Americans (AA) with metastatic colorectal cancer (MCRC) compared to Caucasians (C) when treated with IFL, FOLFOX or IROX in Intergroup N9741
Authors: R. M. Goldberg, H. L. McLeod, D. J. Sargent, R. F. Morton, E. M. Green, C. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, H. C. Pitot, S. R. Alberts
Journal: Journal of Clinical Oncology (2006)

3503 Background: The association between race &amp; toxicity or response to systemic chemotherapy is poorly understood. We correlated relevent polymorphisms with toxicity &amp; outcome data in AA &amp; C patients (Pts) enrolled in N9741, a large randomized MCRC trial. Methods: Toxicity, response rate (RR), time to progression (TTP), overall survival (OS), &amp; dose intensity (DI) were examined as a function of race in 1412 Pts enrolled on IFL, both full and reduced dose, FOLFOX, or IROX including 486 Pts with pharmacogenomic data. Accrual by race permitted comparison of C (n=1297) to AA (n=112). Results: C &amp; AA were similar in disease extent, PS, gender, prior adjuvant treatment, and DI at cycles 1, 3, 6, or 12. The impact of race on RR, toxicity &amp; the distribution of four relevent drug metabolism genotypes are in the table . AA had lower RR overall &amp; in each treatment arm. Lower toxicity rates were seen in AA Pts, mainly due to less diarrhea, as measured by both CTC V2 &amp; patient reported outcome data. These relationships were maintained in multivariate models adjusting for arm, age, gender, &amp; PS. In these multivariate models, the odds ratio between RR and race was 1.72 (p=0.012) (29% AA vs 41% C) &amp; for severe toxicity the odds ratio was 1.76 (p=0.006) (34% AA vs 48% C). Overall, race was not a significant predictor of TTP or OS (p &gt; 0.50 for each). The hazard ratio comparing FOLFOX to IFL for C was 0.67 and for AA was 0.55. TTP for FOLFOX was superior to both IFL and IROX for both C &amp; AA. Significant differences in pharmacogenetic variants were observed between C &amp; AA, although the sample size for investigating the three-way combination of Rx, race, &amp; pharmacogenomics is too small (36 AA) to draw definitive conclusions. Conclusions: It appears that AA have less toxicity &amp; a lower RR than C when treated with standard MCRC regimens. Different frequencies of polymorphisms in genes relevent to drug metabolism may help explain these clinical differences. [Table: see text] [Table: see text]
Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect <i>via</i> Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment
Authors: Fang Li, Yu Wang, Wei-Liang Chen, Dan-Dan Wang, Ye-Juan Zhou, Ben-Gang You, Yang Liu, Chen-Xi Qu, Shu-di Yang, Meng-Tian Chen, Xue-Nong Zhang
Journal: Theranostics (2019)

Targeting tumor angiogenesis pathway via VEGF siRNA (siVEGF) has shown great potential in treating highly malignant and metastatic non-small cell lung cancer (NSCLC). However, anti-angiogenic monotherapy lacked sufficient antitumor efficacy which suffered from malignant tumor proliferation. Therefore, the combined application of siVEGF and chemotherapeutic agents for simultaneous targeting of tumor proliferation and angiogenesis has been a research hotspot to explore a promising NSCLC therapy regimen. Methods: We designed, for the first time, a rational therapy strategy via intelligently co-delivering siVEGF and chemotherapeutics etoposide (ETO) by multi-functional nanoparticles (NPs) directed against the orthotopic NSCLC. These NPs consisted of cationic liposomes loaded with siVEGF and ETO and then coated with versatile polymer PEGylated histidine-grafted chitosan-lipoic acid (PHCL). We then comprehensively evaluated the anti-angiogenic and anti-proliferation efficiency in the in vitro tumor cell model and in bioluminescent orthotopic lung tumor bearing mice model. Results: The NPs co-delivering siVEGF and ETO exhibited tailor-made surface charge reversal features in mimicking tumor extracellular environment with improved internal tumor penetration capacity and higher cellular internalization. Furthermore, these NPs with flexible particles size triggered by intracellular acidic environment and redox environment showed pinpointed and sharp intracellular cargo release guaranteeing adequate active drug concentration in tumor cells. Enhanced VEGF gene expression silencing efficacy and improved tumor cell anti-proliferation effect were demonstrated in vitro. In addition, the PHCL layer improved the stability of these NPs in neutral environment allowing enhanced orthotopic lung tumor targeting efficiency in vivo. The combined therapy by siVEGF and ETO co-delivered NPs for orthotopic NSCLC simultaneously inhibited tumor proliferation and tumor angiogenesis resulting in more significant suppression of tumor growth and metastasis than monotherapy. Conclusion: Combined application of siVEGF and ETO by the multi-functional NPs with excellent and on-demand properties exhibited the desired antitumor effect on the orthotopic lung tumor. Our work has significant potential in promoting combined anti-angiogenesis therapy and chemotherapy regimen for clinical NSCLC treatment.
Circulating tumor DNA to predict response and resistance by anti-PD-1 therapy in Chinese relapsed/refractory classic Hodgkin lymphoma.
Authors: Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengmin Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Yan Xiong, Hui Zhou, Xinhua Du, Xiong Wang, Yuankai Shi
Journal: Journal of Clinical Oncology (2019)

7534 Background: A large fraction of patients with relapsed/refractory (r/r) Classic Hodgkin Lymphoma (cHL) enjoy a beneficial response induced by PD-1. However, no reliable predictive biomarkers for response or resistance are available. Sintilimab, an anti-PD1 agent, has recently demonstrated efficacy and safety in a multi-center, single-arm, phase II study of Chinese patients with r/r cHL (ORIENT-1). The predictive value of circulating tumor DNA (ctDNA) in longitudinal samples from patients in ORIENT-1 was investigated. Methods: A total of 192 plasma samples were collected from 75 patients prior to treatment and during therapy. After ctDNA extraction next-generation sequencing (NGS) was performed using the HiSeq Sequencing System to assess either a 619 or 659 gene panels at an average sequencing depth of 1260×. The panels include frequently mutated genes in cHL and other hematological malignancies. DNA from paired granulocytes was sequenced as presumptive germline control. Results: The genomic profiling of baseline ctDNA revealed a mean allele mutation frequency of 5.47%. Among the most frequently mutated genes in these cHL patients, PCLO and LRP1B are likely unique to Chinese r/r cHL patients. Truncating mutation of B2M, DNMT3, TNFRSF14 and KDM2B were found in patients with acquired resistance, of which TNFRSF14 and KDM2B have not been reported before and need to be confirmed in further study. The baseline ctDNA level was significantly different between objective response group (CR+PR, n = 41, median = 8.72) and non-responder group (SD+PD, n = 9, median = 2.9) ( p= 0.0070) Patients with ctDNA high achieved response earlier than others ( p&lt; 0.05). A drop of 40% in ctDNA after three cycles of therapy confirmed as best cut-off to predict progression associated with clinical benefit, demonstrating 100% specificity. Patients with ctDNA drop ≥40% achieved response significantly earlier (median = 71 days) than others (median = 216 days, p= 0.0074). Conclusions: Our study demonstrated that ctDNA could serve as valuable biomarker for prediction of response or resistance to anti-PD1 immunotherapy.
The Nuclear Matrix Protein SAFA Surveils Viral RNA and Facilitates Immunity by Activating Antiviral Enhancers and Super-enhancers
Authors: Lili Cao, Shengde Liu, Yunfei Li, Guang Yang, Yujie Luo, Siji Li, Hongqiang Du, Yingchi Zhao, Dandan Wang, Jingxuan Chen, Zeming Zhang, Mo Li, Songying Ouyang, Xiang Gao, Yujie Sun, Zekun Wang, Long Yang, Rongtuan Lin, Penghua Wang, Fuping You
Journal: Cell Host & Microbe (2019)
Allergic rhinitis and allergic sensitisation are still increasing among Danish adults
Authors: Katja Biering Leth‐Møller, Tea Skaaby, Allan Linneberg
Journal: Allergy (2019)

Abstract Background Only a limited number of studies have included objective measures of allergic sensitisation (such as skin‐prick test [SPT] and serum specific IgE [sIgE]) when studying time trends in allergic respiratory disease in adults within the current millennium. Methods Five health examination studies of random samples of individuals aged 18‐69 years resident in the Copenhagen region were conducted in 1990‐1991, 2006‐2008, 2010‐2011, 2012‐2015, and 2016‐2017. Allergic sensitisation was defined by sIgE (in 1990‐1991, 2006‐2008, and, 2012‐2015) or SPT (in 2006‐2008, 2010‐2011, and 2016‐2017) to at least one of the allergens: birch, grass, house dust mite, or cat. Allergic rhinitis was defined as sensitisation and self‐reported nasal symptoms. Results The age‐ and sex‐standardised prevalence of sIgE‐defined sensitisation increased from 16% in 1990‐1991, to 26% in 2006‐2008, and to 29% in 2012‐2015. The age‐ and sex‐standardised prevalence of SPT‐defined sensitisation increased from 27% in 2006‐2008, to 28% in 2010‐2011, and to 32% in 2016‐2017. Changes in sIgE‐defined and SPT‐defined allergic rhinitis showed similar increasing trends. Conclusion The prevalence of allergic sensitisation and allergic rhinitis increased in a general adult Danish population over the last three decades and has thus continued to increase in the current millennium.
Development of novel cationic microemulsion as parenteral adjuvant for influenza vaccine
Authors: Sakalanunt Lamaisakul, Angkana Tantituvanont, Vimolmas Lipipun, Garnpimol Ritthidej
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Squalene-based oil-in-water (O/W) emulsions have been used as effective and safe adjuvants in approved influenza vaccines. However, there are concerns regarding the safety and side effects of increasing risk of narcolepsy. In present study, novel O/W microemulsions (MEs) containing wheat germ oil, D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) and Cremophor EL (CreEL) or Solutol HS15 were formulated with/without a cationic surfactant, cetyltrimethylammonium bromide (CTAB) and then sterilized by autoclaving. Their physical properties and biological efficacies were evaluated. The results demonstrated that autoclaving reduced the droplet size to ∼20 nm with narrow size distributions resulting in monodisperse systems with good stability up to 3 years. Hemolytic activity, viscosity, pH, and osmolality were appropriate for parenteral use. Bovine serum albumin (BSA), a model antigen, after mixing with MEs retained the protein integrity, assessed by SDS-PAGE and CD spectroscopy. Greater percentages of 28SC cell viability were observed from CreEL-based MEs. Uptake of FITC-BSA-MEs increased with the increasing concentration of CTAB confirmed by CLSM images. Furthermore, cationic CreEL-based MEs could induce Th1 cytokine synthesis with an increase in TNF-α and IL-12 levels and a decrease in IL-10 level. In vivo immunization study in mice of adjuvants admixed with influenza virus solution revealed that nonionic and selected cationic CreEL-MEs enhanced immune responses as measured by influenza-specific serum antibody titers and hemagglutination inhibition titers. Particularly, cationic CreEL-based ME showed better humoral and cellular immunity with higher IgG2a titer than nonionic CreEL-based ME and antigen alone. No differences in immune responses were observed between mice immunized with selected cationic CreEL-based ME and marketed adjuvant. In addition, the selected ME induced antigen-sparing while retained immune stimulating effects compared to antigen alone. No inflammatory change in muscle fiber structure was observed. Accordingly, the developed cationic CreEL-based ME had potential as novel adjuvant for parenteral influenza vaccine.
Endoscopic management of accidental portal vein puncture during endoscopic ultrasound-guided choledochoduodenostomy
Authors: Carolina Mangas-Sanjuan, Maryana Bozhychko, Juan Martinez, Luis Compañy, Francisco Ruiz, Juan Antonio Casellas, José Ramón Aparicio
Journal: Endoscopy (2019)

A 65-year-old woman was admitted to our department with obstructive jaundice secondary to locally advanced unresectable pancreatic adenocarcinoma. Biliary cannulation attempt was unsuccessful during endoscopic retrograde cholangiopancreatography; therefore, biliary drainage with endoscopic ultrasound (EUS)-guided choledochoduodenostomy (CDS) was planned with palliative intent ([Video 1]).
GPs should provide tailored support to people bereaved by suicide, says NICE
Authors: Jacqui Wise
Journal: BMJ (2019)

GPs should help to identify people who are bereaved or otherwise affected by a suspected suicide and offer them information and tailored support, the UK National Institute for Health and Care Excellence has said.1

NICE’s new quality standard on suicide prevention comes as the latest data from the Office for National Statistics show that the prevalence of suicide in the UK has risen for the first time since 2013.2

People who are bereaved or affected by a suspected suicide are themselves at increased risk of suicide, NICE said, and providing support as soon …