tbuckley/cabot-search huggingface dataset:
Assessment of PD-1 expression in human resting and activated natural killer cells and murine tumor models.
Authors: Sean J. Judge, Cordelia Dunai, Ian R. Sturgill, Kevin M. Stoffel, William J. Murphy, Robert J. Canter
Journal: Journal of Clinical Oncology (2019)

36 Background: Blockade of the PD-1/PD-L1/2 axis has revolutionized cancer therapy. Although reinvigorated PD-1+ T cells are the main effectors in the response to checkpoint blockade, the contribution of Natural Killer (NK) cells to PD-1/PD-L1 inhibition is under debate. While PD-1 has been identified on NK cells, this appears to be restricted to small populations under limited conditions. We sought to evaluate the extent of PD-1 expression in mouse and human resting and activated NK cells. Methods: Human NK cells were isolated from healthy donor PBMCs and cancer patients. Ex vivo activation and proliferation techniques included recombinant human cytokine and feeder line co-culture. Murine NK cells were isolated from splenocytes, and PBMCs from wild type and immunodeficient mice. We assessed NK cell surface markers and intracellular cytokine by flow cytometry, and gene expression by quantitative RT-PCR. Results: Over 21-days of ex vivo expansion, expression of PD-1 or PD-L1 on human NK cells was &lt; 1% at all time points, while TIGIT+ expression increased to &gt; 85%. Conversely, ConA stimulation of T cells increased PD-1 expression with no change in TIGIT expression. QRT-PCR demonstrated absent PD-1 expression in purified NK cells compared to a 5-fold increase in PD-1 gene expression in ConA stimulated PBMCs. PD-1/PD-L1 was also &lt; 1% in the NK92 cell line and &lt; 2.5% in peripheral CD56+CD3- NK cells from patients with soft tissue sarcoma (STS). NK cells from digested freshly resected STS show variable PD-1 ( &lt; 10%) and minimal PD-L1 ( &lt; 1%) expression with a small, but measurable population of intra-tumoral NK cells (1% of immune cells). In vivo mouse studies showed &lt; 5% PD-1+ NK cells in spleen and tumor of CT26 tumor-bearing mice, while PD-L1+ NK cells increased in frequency from spleen (5-35%) to tumor (40-95%) in both wild type BALB/C and SCID mice. Conclusions: In contrast to prior studies, we did not observe a substantial PD-1+ population on human or murine NK cells after multiple activation strategies compared to T cells. Contrary to its application in T cells, our data suggest that PD-1 is not a useful marker for NK cell exhaustion/dysfunction. PD-L1 on NK cells may represent an important link between NK and T cell immunotherapy.
Pulmonary Mycobacterium abscessus: can we identify the road to improved outcomes?
Authors: David W. Connell, Morven Wilkie
Journal: European Respiratory Journal (2019)

<b>The findings of this meta-analysis suggest that specific targeted therapy for <i>Mycobacterium abscessus</i> subspecies <i>abscessus</i> can improve treatment outcomes, and may help to design future antimicrobial drug regimens in this difficult to treat lung infection</b>http://bit.ly/2WOFsRw
Effect of Systolic and Diastolic Blood Pressure on Cardiovascular Outcomes
Authors: Alexander C. Flint, Carol Conell, Xiushui Ren, Nader M. Banki, Sheila L. Chan, Vivek A. Rao, Ronald B. Melles, Deepak L. Bhatt
Journal: New England Journal of Medicine (2019)

The relationship between outpatient systolic and diastolic blood pressure and cardiovascular outcomes remains unclear and has been complicated by recently revised guidelines with two different thresholds (≥140/90 mm Hg and ≥130/80 mm Hg) for treating hypertension.Using data from 1.3 million adults in a general outpatient population, we performed a multivariable Cox survival analysis to determine the effect of the burden of systolic and diastolic hypertension on a composite outcome of myocardial infarction, ischemic stroke, or hemorrhagic stroke over a period of 8 years. The analysis controlled for demographic characteristics and coexisting conditions.The burdens of systolic and diastolic hypertension each independently predicted adverse outcomes. In survival models, a continuous burden of systolic hypertension (≥140 mm Hg; hazard ratio per unit increase in z score, 1.18; 95% confidence interval [CI], 1.17 to 1.18) and diastolic hypertension (≥90 mm Hg; hazard ratio per unit increase in z score, 1.06; 95% CI, 1.06 to 1.07) independently predicted the composite outcome. Similar results were observed with the lower threshold of hypertension (≥130/80 mm Hg) and with systolic and diastolic blood pressures used as predictors without hypertension thresholds. A J-curve relation between diastolic blood pressure and outcomes was seen that was explained at least in part by age and other covariates and by a higher effect of systolic hypertension among persons in the lowest quartile of diastolic blood pressure.Although systolic blood-pressure elevation had a greater effect on outcomes, both systolic and diastolic hypertension independently influenced the risk of adverse cardiovascular events, regardless of the definition of hypertension (≥140/90 mm Hg or ≥130/80 mm Hg). (Funded by the Kaiser Permanente Northern California Community Benefit Program.).
Abstract 15263: Higher Left Atrial Systolic Force is Associated With Insulin Resistance, Dyslipidemia, and Cardiac Hypertrophy in Obese Children
Authors: Kenji Harada, Yukiko Harada, Manatomo Toyono
Journal: Circulation (2016)

Background: Obesity is associated with left atrial (LA) enlargement, but there is little information about LA functional change in children. The purpose of the study is to assess the relationship b...
Gene-Based Dose Optimization in Children
Authors: Laura B. Ramsey, Jacob T. Brown, Susan I. Vear, Jeffrey R. Bishop, Sara L. Van Driest
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose.
The Differences Between Pancreatic Neuroendocrine Tumors Grade 2 and Grade 3—Letter
Authors: Xiao Chen, Zhongqiu Wang
Journal: Clinical Cancer Research (2019)

We have read the interesting study entitled “A combined nomogram model to preoperatively predict histologic grade in pancreatic neuroendocrine tumors” conducted by Liang and colleagues ([1][1]). Their study developed a nomogram model, which included radiomics signature and clinical stage to
Microvascular Disease, Peripheral Artery Disease, and Amputation
Authors: Joshua A. Beckman, Meredith S. Duncan, Scott M. Damrauer, Quinn S. Wells, Joey V. Barnett, David H. Wasserman, Roger J. Bedimo, Adeel A. Butt, Vincent C. Marconi, Jason J. Sico, Hilary A. Tindle, Marc P. Bonaca, Aaron W. Aday, Matthew S. Freiberg
Journal: Circulation (2019)

Background: The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation in a large cohort of veterans to determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease. Methods: Participants in the Veterans Aging Cohort Study were recruited from April 1, 2003 through December 31, 2014. We excluded participants with known prior lower limb amputation. Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors. Results: Among 125 674 veterans without evidence of prior amputation at baseline, the rate of incident amputation over a median of 9.3 years of follow-up was 1.16 per 1000 person-years, yielding a total of 1185 amputations. In time-updated multivariable-adjusted analyses, compared with those without peripheral artery disease or microvascular disease, microvascular disease alone was associated with a 3.7-fold (95% CI, 3.0–4.6) increased risk of amputation; peripheral artery disease alone conferred a 13.9-fold (95% CI, 11.3–17.1) elevated risk of amputation; and the combination of peripheral artery disease and microvascular disease was associated with a 22.7-fold (95% CI, 18.3–28.1) increased risk of amputation. Conclusions: Independent of traditional risk factors, the presence of microvascular disease increases the risk of amputation alone and synergistically increases risk in patients with peripheral artery disease. Further research is needed to understand the mechanisms by which this occurs.
Periodontal Disease Associates With Arterial Inflammation Via Potentiation of a Hematopoietic-Arterial Axis
Authors: Amorina Ishai, Michael T. Osborne, Karim El Kholy, Richard A.P. Takx, Abdelrahman Ali, Neal Yuan, Priscilla Hsue, Thomas E. Van Dyke, Ahmed Tawakol
Journal: JACC. Cardiovascular imaging (2019)
Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging–Alzheimer’s Association Research Framework
Authors: Clifford R. Jack, Terry M. Therneau, Stephen D. Weigand, Heather J. Wiste, David S. Knopman, Prashanthi Vemuri, Val J. Lowe, Michelle M. Mielke, Rosebud O. Roberts, Mary M. Machulda, Jonathan Graff-Radford, David T. Jones, Christopher G. Schwarz, Jeffrey L. Gunter, Matthew L. Senjem, Walter A. Rocca, Ronald C. Petersen
Journal: JAMA Neurology (2019)

A National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker evidence of β-amyloid plaques and tau tangles and not by clinical symptoms.
Evaluation of a multiparametric system able to predict nonsentinel lymph node status in breast cancer patients with a micrometastatic sentinel node assessed by the one step nucleic acidamplification (OSNA) assay.
Authors: Simonetta Buglioni, Marcella Mottolese, Beatrice Casini, Enzo Gallo, Irene Terrenato, Edoardo Pescarmona, Simona Di Filippo, Ferdinando Marandino, Gianluigi Ferretti, Franco Di Filippo
Journal: Journal of Clinical Oncology (2012)

1050 Background: Axillary lymph node dissection (ALND) may not be necessary in women with breast cancer (BC) who have micrometastasis in a sentinel lymph node (SLN), owing to the low risk of non-SLN (NSLN) involvement. In our Institute we validated and adopted the molecular diagnostic tool OSNA based on the quantitative measurement of Cytokeratin 19 (CK19) mRNA.The aims of our work in a subgroup of women with micrometastatic SLN, were: 1) to correlate the copy numbers of CK19 mRNA with the risk of additional positive NSLNs; 2) to assess the relationships between the molecular subtype classification and the probability of a positive ALND; 3) to verify whether a combination of the new above mentioned parameters is able to identify a subgroup of patients with a micrometastatic SLN and a negligible risk of positive NSLNs in whom ALND may be avoided. Methods: The SLN lysates from 709 patients were analyzed by OSNA assay. We considered only patients with a micrometastatic SLN (copy numbers between 250 and 5000/μL) and the probability of having a positive ALND was calculated by the logistic regression model. This series of BC patients were divided into four main subtypes taking in account the BC classification as defined by a combination of estrogen, progesteron receptors and HER2 status. Results: OSNA positivity for micrometastasis was reported in 91/709 cases (12,8%).The number of patients with positive ALND was 20 (22%). The statistical analyses showed that the metastatic involvement of NSLNs is associated with SLNs with a high copy numbers (&gt;2000) of CK19 mRNA together with HER2 subtype. Otherwise none of the luminal A patients with a positive SLN but presenting a copy number &lt;1000, had a positive NSLNs. Conclusions: We showed that biologically-driven analyses may be able to build new models with higher performance in terms of breast cancer axillary status prediction after positive SLN biopsy for micrometastasis. The copy numbers of CK19 mRNA and the molecular subtypes are more advantageous than traditional parameters because they are not pathologist-dependent and therefore they are more reliable and reproducible.
Antibody inhibition of erbB receptors in MLE12, MLE15 and L2 pulmonary alveolar type II cells
Authors: Sandra L. Murray, Lucia D. Pham, Washa Liu, Sujatha Ramadurai, Maryann Volpe, Christiane E. L. Dammann, Heber C. Nielsen
Journal: Cancer Research (2005)

4480  BACKGROUND: Fetal lung maturation involves lung fibroblast-Type II epithelial cell communication through members of the epidermal growth factor receptor (EGFR) family of tyrosine kinases (erbB1, erbB2, erbB3, erbB4). Overexpression of erbB1 and erbB2 occurs in a variety of human cancers. Ligand binding (EGF; neuregulin 1, (NRG)) induces homo- and heterodimer formation followed by receptor phosphorylation and initiation of multiple signal transduction cascades. The specific dimers involved in cell maturation and lung surfactant synthesis are unknown. Our earlier work showed that several erbB receptor antibodies reduced ligand-induced choline incorporation into DSPC (a measure of surfactant synthesis) in the human lung epithelial carcinoma line, A549. Anti-erbB3 and 4 alone or B1/4 together decreased DSPC synthesis induced by EGF, NRG, or fibroblast conditioned media (FCM). Anti-erbB2 decreased both NRG and FCM induction. Anti-erbB1 alone was ineffective in EGF-treated cells, reduced synthesis in NRG and FCM-treated cells but was most effective in combination with anti-erbB4. HYPOTHESIS: Antibodies directed against erbB receptors prevent dimer formation leading to tyrosine phosphorylation necessary for DSPC synthesis in MLE12 and MLE15 murine tumor-derived vs normal rat L2 cells. METHODS: MLE12 and MLE15 cells were derived from SV40 transgenic mouse pulmonary tumors; L2 cells originated from normal adult rat lung epithelia. After incubation with blocking antibodies directed against extracellular epitopes of the four erbB receptors, cells were incubated with EGF (10ng/ml), NRG(10nM) or FCM plus 3H-choline overnight to measure DSPC synthesis. RESULTS: In MLE12 cells anti-erbB3 decreased DSPC synthesis in all ligand-treated cells by 25-35%. Anti-erbB1/4 was effective only in FCM-treated cells (40% decrease); anti-erbB2/4 reduced synthesis in all ligand-treated cells by 65%. In normal L2 cells, NRG and FCM stimulated incorporation about 50 %. Preincubation with anti-erbB3 or 4 did not inhibit but further stimulated incorporation up to 200% (NRG) and 300% (FCM). CONCLUSIONS: A549, MLE12 and L2 cells have all been utilized as pulmonary epithelial cell models. Although erbB3 lacks specific tyrosine kinase sites, these results support its crucial role as a heterodimer partner leading to surfactant synthesis. Inhibitory anti-erbB3 and 4, directed against neuregulin-binding receptors, are particularly effective, alone or in combination with anti-erbB2, in the tumor-derived lines. FCM-treated cells were less sensitive to inhibition. In contrast, these same antibodies were stimulatory in the cells derived from normal adult lung tissue, particularly in the presence of FCM, suggesting that FCM contains other factors as well as neuregulin. NIH HL37930, HL04436, Hood and Peabody Foundations.
Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease
Authors: Antigoni Morou, Elsa Brunet-Ratnasingham, Mathieu Dubé, Roxanne Charlebois, Eloi Mercier, Sam Darko, Nathalie Brassard, Krystelle Nganou-Makamdop, Sahaana Arumugam, Gabrielle Gendron-Lepage, Lifei Yang, Julia Niessl, Amy E. Baxter, James M. Billingsley, Premeela A. Rajakumar, François Lefebvre, R. Paul Johnson, Cécile Tremblay, Jean-Pierre Routy, Richard T. Wyatt, Andrés Finzi, Daniel C. Douek, Daniel E. Kaufmann
Journal: Nature Immunology (2019)
Abstract 13898: Intravenous Administration of Xenogenic Adipose-Derived Mesenchymal Stem Cells (ADMSC) and ADMSC-Derived Exosomes Markedly Reduced Brain Infarct Volume and Preserved Neurological Function in Rat After Acute Ischemic Stroke
Authors: Hon-Kan Yip, Christopher Glenn Wallace, Pei-Lin Shao
Journal: Circulation (2017)

Introduction: We tested the hypothesis that combined xenogenic (from mini-pig) adipose-derived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) ...
Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours
Authors: David T. W. Jones, Ana Banito, Thomas G. P. Grünewald, Michelle Haber, Natalie Jäger, Marcel Kool, Till Milde, Jan J. Molenaar, Arash Nabbi, Trevor J. Pugh, Gudrun Schleiermacher, Malcolm A. Smith, Frank Westermann, Stefan M. Pfister
Journal: Nature reviews. Cancer (2019)
GPRC5b Modulates Inflammatory Response in Glomerular Diseases via NF-κB Pathway
Authors: Sonia Zambrano, Katja Möller-Hackbarth, Xidan Li, Patricia Q. Rodriguez, Emmanuelle Charrin, Angelina Schwarz, Jenny Nyström, Annika Östman Wernerson, Mark Lal, Jaakko Patrakka
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Mechanisms regulating inflammatory response in glomeruli are poorly understood. In this study, the authors identify a novel G protein–coupled receptor (GPCR) that is highly enriched in podocytes, called Gprc5b. Gprc5b is upregulated in common human glomerular diseases, such as IgA nephropathy, lupus nephritis, and diabetic nephropathy. Studies in knockout animals and human podocytes grown in culture show that Gprc5b promotes glomerular inflammation via regulation of NF- κ B pathway in podocytes. Upregulation of Gprc5b in human diseases suggests that this mechanism may play an important role in the pathogenesis of common glomerulopathies. Background Inflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood. Methods We performed large-scale gene expression profiling of glomerulus-associated G protein–coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies. The expression of Gprc5b in disease was analyzed using quantitative PCR and immunofluorescence, and by analyzing published microarray data sets. In vivo studies were carried out in a podocyte-specific Gprc5b knockout mouse line. Mechanistic studies were performed in cultured human podocytes. Results We identified an orphan GPCR, Gprc5b, as a novel gene highly enriched in podocytes that was significantly upregulated in common human glomerulopathies, including diabetic nephropathy, IgA nephropathy, and lupus nephritis. Similar upregulation of Gprc5b was detected in LPS-induced nephropathy in mice. Studies in podocyte-specific Gprc5b knockout mice showed that Gprc5b was not essential for normal development of the glomerular filtration barrier. However, knockout mice were partially protected from LPS-induced proteinuria and recruitment of inflammatory cells. Mechanistically, RNA sequencing in Gprc5b knockouts mice and experiments in cultured human podocytes showed that Gpr5cb regulated inflammatory response in podocytes via NF- κ B signaling. Conclusions GPRC5b is a novel podocyte-specific receptor that regulates inflammatory response in the glomerulus by modulating the NF- κ B signaling pathway. Upregulation of Gprc5b in human glomerulopathies suggests that it may play a role in their pathogenesis.
GP gets eight month suspension after clinical errors in treatment of four patients
Authors: Clare Dyer
Journal: BMJ (2019)

An experienced GP and practice partner has been suspended from the UK medical register for eight months after a tribunal found that he had committed serious clinical errors in the treatment of four patients.

Simon Caswell was reported to the General Medical Council in 2017 by his practice partner and by a locum GP who was acting as the practice manager at the Beehive Surgery in Bolton. Caswell represented himself before the medical practitioners tribunal in Manchester.

He was found to have inappropriately increased a patient’s fentanyl patch from 50 to 100 μg in one step, when the British National Formulary advises changing dosage by increments of no more than 12.5 …
15-Lipoxygenase 1 in nasal polyps promotes CCL26/eotaxin 3 expression through extracellular signal-regulated kinase activation
Authors: Zhipeng Li, Ming Zeng, Yanhan Deng, Jinming Zhao, Xiuxia Zhou, John B. Trudeau, Ezequiel Goldschmidt, John A. Moore, Hongwei Chu, Weitian Zhang, Shankai Yin, Zheng Liu, Y. Peter Di, Stella E. Lee, Sally E. Wenzel
Journal: Journal of Allergy and Clinical Immunology (2019)
Are Platelets the Primary Target of Aspirin's Remarkable Anticancer Activity?
Authors: Lenard M. Lichtenberger, K. Vinod Vijayan
Journal: Cancer Research (2019)

Aspirin, when administered at low doses, has emerged as a powerful anticancer drug due to both chemopreventive activity against many forms of cancer and its ability to block metastases when administered postdiagnosis. Platelets, which are often elevated in circulation during the latter stages of cancer, are known to promote epithelial-mesenchymal transition, cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. Low-dose aspirin has been demonstrated to block this procarcinogenic action of platelets. In this article, we present evidence that aspirin's unique ability to irreversibly inhibit platelet cyclooxygenase-1 is a key mechanism by which aspirin exerts anticancer activity.
JAK2V617F Variant Allele Frequency Identifies Patients with Polycythemia Vera (PV) at High Risk for Venous Thrombosis
Authors: Paola Guglielmelli, Giacomo Coltro, Giuseppe Gaetano Loscocco, Benedetta Sordi, Francesco Mannelli, Chiara Paoli, Ilaria Marone, Alessandro Pancrazzi, Francesca Gesullo, Carmela Mannarelli, Tiziano Barbui, Alessandro M. Vannucchi
Journal: Blood (2018)