tbuckley/cabot-search huggingface dataset:
CPR: The P Stands for Plumber's Helper
Authors: Keith G. Lurie, Clinton Lindo, Jerome Chin
Journal: JAMA (1990)

To the Editor.—  Through novel methods of cardiac resuscitation exist, the traditional cardiopulmonary resuscitation (CPR) techniques recommended by the American Heart Association have a proven track record. 1 This is not the case, however, in all families. We describe a 65-year-old Iranian man with severe triple-vessel coronary artery disease documented by cardiac catheterization in Iran in 1985. Since his third myocardial infarction he has been limited by severe one-block angina. Unable to afford bypass surgery, his condition was managed with antianginal medications. One recent Saturday evening after dinner, while watching television, the patient collapsed in front of his family. He was unrousable. His son, poorly trained in traditional CPR, attempted to ventilate his father, but the patient did not respond. The son then attempted manual chest compression, but his father reportedly remained pulseless and breathless. The son then remembered that his mother had resuscitated her husband 6 months earlier with
Neutralizing Murine TGFβR2 Promotes a Differentiated Tumor Cell Phenotype and Inhibits Pancreatic Cancer Metastasis
Authors: Katherine T. Ostapoff, Bercin Kutluk Cenik, Miao Wang, Risheng Ye, Xiaohong Xu, Desiree Nugent, Moriah M. Hagopian, Mary Topalovski, Lee B. Rivera, Kyla D. Carroll, Rolf A. Brekken
Journal: Cancer Research (2014)

Abstract Elevated levels of TGFβ are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGFβ pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGFβ remains challenging because TGFβ has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGFβ promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that neutralizing the activity of murine TGFβ receptor 2 using a monoclonal antibody (2G8) has potent antimetastatic activity in orthotopic human tumor xenografts, syngeneic tumors, and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density, and vascular function. These stromal-specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGFβ signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGFβ-dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. Cancer Res; 74(18); 4996–5007. ©2014 AACR.
Effect of Pentavac and measles-mumps-rubella (MMR) vaccination on the intestine
Authors: B Thjodleifsson
Journal: Gut (2002)

<h3>ABSTRACT</h3> Covalent inhibitors of the KRAS<sup>G12C</sup> oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and likely to limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and to predict drug combinations that circumvent resistance, we used a mass spectrometry-based quantitative temporal proteomics and bioinformatics workflow to profile the temporal proteomic response to KRAS<sup>G12C</sup> inhibition in pancreatic and lung cancer 2D and 3D cellular models. We quantified 10,805 proteins across our datasets, representing the most comprehensive KRASi proteomics effort to date. Our data reveal common mechanisms of acute and long-term response between KRAS<sup>G12C</sup>-driven tumors. To facilitate discovery in the cancer biology community, we generated an interactive ‘KRASi proteome’ website (https://manciaslab.shinyapps.io/KRASi/). Based on these proteomic data, we identified potent combinations of KRASi with PI3K, HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using our quantitative temporal proteomics-bioinformatics platform, we have comprehensively characterized the proteomic adaptations to KRASi and identified combinatorial regimens to induce cytotoxicity with potential therapeutic utility.
A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee
Authors: J. Bruce Moseley, Kimberly O'Malley, Nancy J. Petersen, Terri J. Menke, Baruch A. Brody, David H. Kuykendall, John C. Hollingsworth, Carol M. Ashton, Nelda P. Wray
Journal: New England Journal of Medicine (2002)

Many patients report symptomatic relief after undergoing arthroscopy of the knee for osteoarthritis, but it is unclear how the procedure achieves this result. We conducted a randomized, placebo-controlled trial to evaluate the efficacy of arthroscopy for osteoarthritis of the knee.
Strong Heterogeneity in Mutation Rate Causes Misleading Hallmarks of Natural Selection on Indel Mutations in the Human Genome
Authors: Erika M. Kvikstad, Laurent Duret
Journal: Molecular Biology and Evolution (2013)

Elucidating the mechanisms of mutation accumulation and fixation is critical to understand the nature of genetic variation and its contribution to genome evolution. Of particular interest is the effect of insertions and deletions (indels) on the evolution of genome landscapes. Recent population-scaled sequencing efforts provide unprecedented data for analyzing the relative impact of selection versus nonadaptive forces operating on indels. Here, we combined McDonald–Kreitman tests with the analysis of derived allele frequency spectra to investigate the dynamics of allele fixation of short (1–50 bp) indels in the human genome. Our analyses revealed apparently higher fixation probabilities for insertions than deletions. However, this fixation bias is not consistent with either selection or biased gene conversion and varies with local mutation rate, being particularly pronounced at indel hotspots. Furthermore, we identified an unprecedented number of loci with evidence for multiple indel events in the primate phylogeny. Even in nonrepetitive sequence contexts (a priori not prone to indel mutations), such loci are 60-fold more frequent than expected according to a model of uniform indel mutation rate. This provides evidence of as yet unidentified cryptic indel hotspots. We propose that indel homoplasy, at known and cryptic hotspots, produces systematic errors in determination of ancestral alleles via parsimony and advise caution interpreting classic selection tests given the strong heterogeneity in indel rates across the genome. These results will have great impact on studies seeking to infer evolutionary forces operating on indels observed in closely related species, because such mutations are traditionally presumed homoplasy-free.
Deteriorated housing contributes to high cockroach allergen levels in inner-city households.
Authors: Virginia A Rauh, Ginger R Chew, Robin S Garfinkel
Journal: Environmental Health Perspectives (2002)

The high prevalence of childhood asthma in low-income, inner-city populations is not fully understood but has been at least partly attributed to the disproportionate exposures associated with socioeconomic disadvantage. The contribution of indoor allergens to asthma is well documented, but links between socioeconomic disadvantage and indoor allergen levels are not clear. We investigated levels of cockroach allergens (Bla g 2) in a sample of 132 Dominican or African American low-income households with young children in northern Manhattan in New York City (40% were receiving public assistance) to determine whether the distribution of allergens is a function of housing deterioration. Deterioration was measured by the presence and number of physical housing problems (holes in the ceilings and walls, water damage, etc.). More than 50% of the sample had two or more types of housing dilapidation, and 67% of the sample reported cockroach sightings in their homes. Samples of dust were collected from kitchen and bedroom surfaces. We hypothesized that the greater the dilapidation, the higher the allergen levels, independent of income, sociocultural factors, and pest-control methods. In addition, we hypothesized that the homes of families characterized by frequent moves (23.5%) would have higher allergen levels than more stable families. Results showed significant positive associations between housing deterioration and allergen levels in kitchens, after adjusting for income and ethnicity, with independent effects of residential stability (p< 0.05). Bedroom allergen levels were associated with housing instability (p < 0.01) and ethnicity (p< 0.01). Findings demonstrated that indoor household allergen levels are related to degree of household disrepair, after adjusting for individual family attributes, suggesting that social-structural aspects of housing may be appropriate targets for public health interventions designed to reduce allergen exposure.
Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life
Authors: T Tschernig
Journal: Thorax (2001)

Background-Dendritic cells (DCs) in the mucosa of the respiratory tract might be involved in the early development of pulmonary allergy or tolerance.To date, little is known about when the first DCs occur in human airways.Methods-Specimens of the distal trachea from patients who had died from sudden death in the first year of life (n=29) and in older age groups (n=59) as well as from those who had died from respiratory tract infections in the first year of life (n=8) were examined by immunohistochemistry. Transmission electron microscopy was performed in additional samples from two adults.Results-In the sudden death subgroup DCs were absent in 76% of those who died in the first year of life but were present in 53 of the 59 older cases.All infants who had died of respiratory infectious diseases had DCs in the tracheal mucosa.Conclusions-Mature DCs are not constitutively present in the human tracheobronchial mucosa in the first year of life, but their occurrence seems to be triggered by infectious stimuli.These data support the hypothesis that DCs play a crucial role in immunoregulation in early childhood.
The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic Cells
Authors: Ralph M. Steinman, Shannon Turley, Ira Mellman, Kayo Inaba
Journal: The Journal of Experimental Medicine (2000)

What makes a protein immunogenic, particularly for strong T cell-mediated immunity?To a first approximation, this determination seems to be made by dendritic cells (DCs).Immature DCs, as in skin (1-4), lung ( 5), blood (6, 7), and spleen (7, 8), take up proteins, immune complexes, microbes, and dying cells.However, in order to use these antigens to stimulate a T cell response, the DCs must undergo a characteristic process of terminal differentiation called "maturation."The known stimuli for DC maturation are numerous and include inflammatory cytokines, CD40 ligand (CD40L), viral and microbial constituents such as doublestranded RNA and LPS, and certain CpG oligonucleotides. DC Maturation as a Control Point in the Initiation of ImmunityMaturation changes DCs in many ways that help explain their potent immunogenicity.Examples include de novo expression of T cell costimulatory molecules like CD86 (9, 10); the capacity to produce 12) and resist immunosuppression by IL-10 (13); the development of a new repertoire of chemokine receptors, especially CCR7 (14-17), that guide entry into lymphatics and migration to the T cell areas (18); the production of DC survival and stimulatory molecules like CD40 and TNF-related activation-induced cytokine receptor (TRANCE-R) (19,20); and a redistribution of MHC class II molecules from lysosomes to the cell surface (21,22).
An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission
Authors: Alexander W. Tarr, Pierre Lafaye, Luke Meredith, Laurence Damier-Piolle, Richard A. Urbanowicz, Annalisa Meola, Jean-Luc Jestin, Richard J. P. Brown, Jane A. McKeating, Felix A. Rey, Jonathan K. Ball, Thomas Krey
Journal: Hepatology (2013)

Severe liver disease caused by chronic hepatitis C virus is the major indication for liver transplantation. Despite recent advances in antiviral therapy, drug toxicity and unwanted side effects render effective treatment in liver-transplanted patients a challenging task. Virus-specific therapeutic antibodies are generally safe and well-tolerated, but their potential in preventing and treating hepatitis C virus (HCV) infection has not yet been realized due to a variety of issues, not least high production costs and virus variability. Heavy-chain antibodies or nanobodies, produced by camelids, represent an exciting antiviral approach; they can target novel highly conserved epitopes that are inaccessible to normal antibodies, and they are also easy to manipulate and produce. We isolated four distinct nanobodies from a phage-display library generated from an alpaca immunized with HCV E2 glycoprotein. One of them, nanobody D03, recognized a novel epitope overlapping with the epitopes of several broadly neutralizing human monoclonal antibodies. Its crystal structure revealed a long complementarity determining region (CD3) folding over part of the framework that, in conventional antibodies, forms the interface between heavy and light chain. D03 neutralized a panel of retroviral particles pseudotyped with HCV glycoproteins from six genotypes and authentic cell culture–derived particles by interfering with the E2-CD81 interaction. In contrast to some of the most broadly neutralizing human anti-E2 monoclonal antibodies, D03 efficiently inhibited HCV cell-to-cell transmission. Conclusion : This is the first description of a potent and broadly neutralizing HCV-specific nanobody representing a significant advance that will lead to future development of novel entry inhibitors for the treatment and prevention of HCV infection and help our understanding of HCV cell-to-cell transmission. (Hepatology 2013;53:932–939)
Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8
Authors: Dipyaman Ganguly, Georgios Chamilos, Roberto Lande, Josh Gregorio, Stephan Meller, Valeria Facchinetti, Bernhard Homey, Franck J. Barrat, Tomasz Zal, Michel Gilliet
Journal: The Journal of Experimental Medicine (2009)

Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid–recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA–LL37 complexes activate TLR7 and, like self-DNA–LL37 complexes, trigger the secretion of IFN-α without inducing maturation or the production of IL-6 and TNF-α. In contrast to self-DNA–LL37 complexes, self-RNA–LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-α and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA–LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.
Targeting cancer vasculature via endoglin/CD105: a novel antibody-based diagnostic and therapeutic strategy in solid tumours
Authors: E. Fonsatti, H. J.M. Nicolay, M. Altomonte, A. Covre, M. Maio
Journal: Cardiovascular Research (2009)

Endoglin/CD105 is well acknowledged as being the most reliable marker of proliferation of endothelial cells, and it is overexpressed on tumour neovasculature. Our current knowledge of its structure, physiological role, and tissue distribution suggests that targeting of endoglin/CD105 is a novel and powerful diagnostic and therapeutic strategy in human malignancies, through the imaging of tumour-associated angiogenesis and the inhibition of endothelial cell functions related to tumour angiogenesis. Among biotherapeutic agents, monoclonal antibodies have shown a major impact on the clinical course of human malignancies of different histotypes. Along this line, the potential efficacy of anti-endoglin/CD105 antibodies and their derivatives for clinical purposes in cancer is supported by a large body of available pre-clinical in vitro and in vivo data. In this review, the main findings supporting the translation of antibody-based endoglin/CD105 targeting from pre-clinical studies to clinical applications in human cancer are summarized and discussed.
Effect of Injectable Alginate Implant on Cardiac Remodeling and Function After Recent and Old Infarcts in Rat
Authors: Natali Landa, Liron Miller, Micha S. Feinberg, Radka Holbova, Michal Shachar, Inbar Freeman, Smadar Cohen, Jonathan Leor
Journal: Circulation (2008)

Background— Adverse cardiac remodeling and progression of heart failure after myocardial infarction are associated with excessive and continuous damage to the extracellular matrix. We hypothesized that injection of in situ–forming alginate hydrogel into recent and old infarcts would provide a temporary scaffold and attenuate adverse cardiac remodeling and dysfunction. Methods and Results— We developed a novel absorbable biomaterial composed of calcium-crosslinked alginate solution, which displays low viscosity and, after injection into the infarct, undergoes phase transition into hydrogel. To determine the outcome of the biomaterial after injection, calcium-crosslinked biotin-labeled alginate was injected into the infarct 7 days after anterior myocardial infarction in rat. Serial histology studies showed in situ formation of alginate hydrogel implant, which occupied up to 50% of the scar area. The biomaterial was replaced by connective tissue within 6 weeks. Serial echocardiography studies before and 60 days after injection showed that injection of alginate biomaterial into recent (7 days) infarct increased scar thickness and attenuated left ventricular systolic and diastolic dilatation and dysfunction. These beneficial effects were comparable and sometimes superior to those achieved by neonatal cardiomyocyte transplantation. Moreover, injection of alginate biomaterial into old myocardial infarction (60 days) increased scar thickness and improved systolic and diastolic dysfunction. Conclusions— We show for the first time that injection of in situ–forming, bioabsorbable alginate hydrogel is an effective acellular strategy that prevents adverse cardiac remodeling and dysfunction in recent and old myocardial infarctions in rat.
Relationship between body mass index, age and upper airway measurements in snorers and sleep apnoea patients
Authors: P Mayer, JL Pepin, G Bettega, D Veale, G Ferretti, C Deschaux, P Levy
Journal: European Respiratory Journal (1996)

Anatomical pharyngeal and craniofacial abnormalities have been reported using upper airway imaging in snorers with or without obstructive sleep apnoea (OSA). However, the influences of the age and weight of the patient on these abnormalities remain to be established. The aim of this study was, therefore, to evaluate in a large population of snorers with or without OSA, the relationship between body mass index (BMI), age and upper airway morphology. One hundred and forty patients were referred for assessment of a possible sleep-related breathing disorder and had complete polysomnography, cephalometry and upper airway computed tomography. For the whole population, OSA patients had more upper airway abnormalities than snorers. When subdivided for BMI and age, however, only lean or younger OSA patients were significantly different from snorers as regards their upper airway anatomy. The shape of the oropharynx and hypopharynx changed significantly with BMI both in OSA patients and snorers, being more spherical in the highest BMI group due mainly to a decrease in the transverse axis. On the other hand, older patients (> 63 yrs), whether snorers or apnoeics, had larger upper airways at all pharyngeal levels than the youngest group of patients (< 52 yrs). For the total group of patients, upper airway variables explained 26% of the variance in apnoea/hypopnoea index (AHI), whereas in lean (BMI < 27 kg.m-2) or youngest (age < 52 yrs) subjects upper airway variables explained, respectively 69 and 55% of the variance in AHI. In conclusion, in lean or young subjects, upper airway abnormalities explain a major part of the variance in apnoea/hypopnoea index and are likely to play an important physiopathogenic role. This study also suggests that the shape of the pharyngeal lumen in awake subjects is more dependent on body mass index than on the presence of obstructive sleep apnoea. Further investigation looking at upper airway imaging for surgical selection in obstructive sleep apnoea should focus on lean and young patients.
Differential Expression of the Intermediate Filament Protein Nestin during Renal Development and Its Localization in Adult Podocytes
Authors: Jing Chen, Scott Boyle, Min Zhao, Wei Su, Keiko Takahashi, Linda Davis, Mark DeCaestecker, Takamune Takahashi, Matthew D. Breyer, Chuan-Ming Hao
Journal: Journal of the American Society of Nephrology (2006)

Nestin, an intermediate filament protein, is widely used as stem cell marker. Nestin has been shown to interact with other cytoskeleton proteins, suggesting a role in regulating cellular cytoskeletal structure. These studies examined renal nestin localization and developmental expression in mice. In developing kidney, anti-nestin antibody revealed strong immunoreactivity in vascular cleft of the S-shaped body and vascular tuft of capillary loop-stage glomerulus. The nestin-positive structures also were labeled by endothelial cell markers FLK1 and CD31 in immature glomeruli. Nestin was not detected in epithelial cells of immature glomeruli. In contrast, in mature glomerular, nestin immunoreactivity was observed only outside laminin-positive glomerular basement membrane, and co-localized with nephrin, consistent with podocyte nestin expression. In adult kidney, podocytes were the only cells that exhibited persistent nestin expression. Nestin was not detected in ureteric bud and its derivatives throughout renal development. Cell lineage studies, using a nestin promoter-driven Cre mouse and a ROSA26 reporter mouse, showed a strong beta-galactosidase activity in intermediate mesoderm in an embryonic day 10 embryo and all of the structures except those that were derived from ureteric bud in embryonic kidney through adult kidney. These studies show that nestin is expressed in progenitors of glomerular endothelial cells and renal progenitors that are derived from metanephric mesenchyme. In the adult kidney, nestin expression is restricted to differentiated podocytes, suggesting that nestin could play an important role in maintaining the structural integrity of the podocytes.
1208 EVALUATION OF NS3 AMINO ACID VARIANTS IN A PHASE 1B STUDY OF GENOTYPE 1 (GT1) AND GT3 INFECTED PATIENTS WITH THE HCV PROTEASE INHIBITOR, MK-5172
Authors: J.M. Strizki, R.J.O. Barnard, C. Cheney, C. McHale, D. Graham, A. Himmelberger, A. Petry, I. Fraser, R. Nachbar, D.J. Hazuda
Journal: Journal of Hepatology (2012)