tbuckley/cabot-search huggingface dataset:
Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women's Hospital Tumor Staging for Cutaneous Squamous Cell Carcinoma
Authors: Pritesh S. Karia, Anokhi Jambusaria-Pahlajani, David P. Harrington, George F. Murphy, Abrar A. Qureshi, Chrysalyne D. Schmults
Journal: Journal of Clinical Oncology (2013)

To compare American Joint Committee on Cancer (AJCC), International Union Against Cancer (UICC), and Brigham and Women's Hospital (BWH) tumor (T) staging systems for cutaneous squamous cell carcinoma and validate BWH staging against prior data.Primary tumors diagnosed from 2000 to 2009 at BWH (n = 1,818) were analyzed. Poor outcomes (local recurrence [LR], nodal metastasis [NM], and disease-specific death [DSD]) were analyzed by T stage with regard to each staging system's distinctiveness (outcome differences between stages), homogeneity (outcome similarity within stages), and monotonicity (outcome worsening with increasing stage).AJCC and UICC T3 and T4 were indistinct with overlapping 95% CIs for 10-year cumulative incidences of poor outcomes, but all four BWH stages were distinct. AJCC and UICC high-stage tumors (T3/T4) were rare at 0.3% and 3% of the cohort, respectively. Most poor outcomes occurred in low stages (T1/T2; AJCC: 86% [95% CI, 77% to 91%]; UICC: 70% [61% to 79%]) resulting in heterogeneous outcomes in T1/T2. Conversely, in BWH staging, only 5% of tumors were high stage (T2b/T3), but they accounted for 60% (95% CI, 50% to 69%) of poor outcomes (70% of NMs and 83% of DSDs) indicating superior homogeneity and monotonicity as previously defined. Cumulative incidences of poor outcomes were low for BWH low-stage (T1/T2a) tumors (LR, 1.4% [95% CI, 1% to 2%]; NM, 0.6% [95% CI, 0% to 1%]; DSD, 0.2% [95% CI, 0% to 0.5%]) and higher for high-stage (T2b/T3) tumors (LR, 24% [95% CI, 16% to 34%]; NM, 24% [95% CI, 16% to 34%]; and DSD, 16% [95% CI, 10% to 25%], which validated an earlier study of an alternative staging system.BWH staging offers improved distinctiveness, homogeneity, and monotonicity over AJCC and UICC staging. Population-based validation is needed. BWH T2b/T3 tumors define a high-risk group requiring further study for optimal management.
Evolutionary History of True Crabs (Crustacea: Decapoda: Brachyura) and the Origin of Freshwater Crabs
Authors: Ling Ming Tsang, Christoph D. Schubart, Shane T. Ahyong, Joelle C.Y. Lai, Eugene Y.C. Au, Tin-Yam Chan, Peter K.L. Ng, Ka Hou Chu
Journal: Molecular Biology and Evolution (2014)

Crabs of the infra-order Brachyura are one of the most diverse groups of crustaceans with approximately 7,000 described species in 98 families, occurring in marine, freshwater, and terrestrial habitats. The relationships among the brachyuran families are poorly understood due to the high morphological complexity of the group. Here, we reconstruct the most comprehensive phylogeny of Brachyura to date using sequence data of six nuclear protein-coding genes and two mitochondrial rRNA genes from more than 140 species belonging to 58 families. The gene tree confirms that the “Podotremata,” are paraphyletic. Within the monophyletic Eubrachyura, the reciprocal monophyly of the two subsections, Heterotremata and Thoracotremata, is supported. Monophyly of many superfamilies, however, is not recovered, indicating the prevalence of morphological convergence and the need for further taxonomic studies. Freshwater crabs were derived early in the evolution of Eubrachyura and are shown to have at least two independent origins. Bayesian relaxed molecular methods estimate that freshwater crabs separated from their closest marine sister taxa ∼135 Ma, that is, after the break up of Pangaea (∼200 Ma) and that a Gondwanan origin of these freshwater representatives is untenable. Most extant families and superfamilies arose during the late Cretaceous and early Tertiary.
Birth rate drops when obstetricians leave town
Authors: Roger Dobson
Journal: BMJ (2007)

New research shows that when obstetricians and gynaecologists are away at national conferences the number of births drops ( Social Science and Medicine 2007 Jun 27 doi: 10.1016/j.socscimed.2007.05.034).

Researchers found that the number of births dropped by up to 4% during five day key annual conferences in the United States and Australia, with nearly 1000 births affected.

“Since it is unlikely that parents take these conferences into account when conceiving their child, this suggests that medical professionals are timing births to suit their conference schedule,” say Joshua …
TRPV4 Forms a Novel Ca <sup>2+</sup> Signaling Complex With Ryanodine Receptors and BK <sub>Ca</sub> Channels
Authors: Scott Earley, Thomas J. Heppner, Mark T. Nelson, Joseph E. Brayden
Journal: Circulation Research (2005)

Vasodilatory factors produced by the endothelium are critical for the maintenance of normal blood pressure and flow. We hypothesized that endothelial signals are transduced to underlying vascular smooth muscle by vanilloid transient receptor potential (TRPV) channels. TRPV4 message was detected in RNA from cerebral artery smooth muscle cells. In patch-clamp experiments using freshly isolated cerebral myocytes, outwardly rectifying whole-cell currents with properties consistent with those of expressed TRPV4 channels were evoked by the TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) (5 micromol/L) and the endothelium-derived arachidonic acid metabolite 11,12 epoxyeicosatrienoic acid (11,12 EET) (300 nmol/L). Using high-speed laser-scanning confocal microscopy, we found that 11,12 EET increased the frequency of unitary Ca2+ release events (Ca2+ sparks) via ryanodine receptors located on the sarcoplasmic reticulum of cerebral artery smooth muscle cells. EET-induced Ca2+ sparks activated nearby sarcolemmal large-conductance Ca2+-activated K+ (BKCa) channels, measured as an increase in the frequency of transient K+ currents (referred to as "spontaneous transient outward currents" [STOCs]). 11,12 EET-induced increases in Ca2+ spark and STOC frequency were inhibited by lowering external Ca2+ from 2 mmol/L to 10 micromol/L but not by voltage-dependent Ca2+ channel inhibitors, suggesting that these responses require extracellular Ca2+ influx via channels other than voltage-dependent Ca2+ channels. Antisense-mediated suppression of TRPV4 expression in intact cerebral arteries prevented 11,12 EET-induced smooth muscle hyperpolarization and vasodilation. Thus, we conclude that TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels that elicits smooth muscle hyperpolarization and arterial dilation via Ca2+-induced Ca2+ release in response to an endothelial-derived factor.
Targeted Drug and Gene Delivery Systems for Lung Cancer Therapy
Authors: Sneha Sundaram, Ruchit Trivedi, Chandrasekar Durairaj, Rajagopal Ramesh, Balamurali K. Ambati, Uday B. Kompella
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone–releasing hormone (LHRH) agonist, and its combination in vivo with RGD peptide conjugated nanoparticles encapsulating an antiangiogenic, anti–vascular endothelial growth factor (VEGF) intraceptor (Flt23k; RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice. Experimental Design: The in vitro and in vivo efficacy of the deslorelin-docetaxel conjugate was evaluated in H1299 cells and xenografts in athymic nude mice. Coadministration of deslorelin-docetaxel conjugate and RGD-Flt23k-NP was tested in vivo in mice. Tumor inhibition, apoptosis, and VEGF inhibition were estimated in each of the treatment groups. Results: The conjugate enhanced in vitro docetaxel efficacy by 13-fold in H1299 cells compared with docetaxel at 24 hours, and this effect was inhibited following reduction of LHRH receptor expression by an antisense oligonucleotide. Combination of the conjugate with the RGD-Flt23k-NP in vivo resulted in an 82- and 15-fold tumor growth inhibition on day 39 following repeated weekly i.v. injections and a single intratumoral (i.t.) injection, respectively. These effects were significantly greater than individual targeted therapies or docetaxel alone. Similarly, apoptotic indices for the combination therapy were 14% and 10% in the i.v. and i.t. groups, respectively, and higher than the individual therapies. Combination therapy groups exhibited greater VEGF inhibition in both the i.v. and i.t. groups. Conclusions: Docetaxel efficacy was enhanced by LHRH receptor–targeted deslorelin conjugate and further improved by combination with targeted antiangiogenic nanoparticle gene therapy. Combination of novel targeted therapeutic approaches described here provides an attractive alternative to the current treatment options for lung cancer therapy. (Clin Cancer Res 2009;15(23):7299–308)
Development of High-density DNA Microarray Membrane for Profiling Smoke- and Hydrogen Peroxide-induced Genes in a Human Bronchial Epithelial Cell Line
Authors: KEN YONEDA, KONAN PECK, MARY MANN-JONG CHANG, KEN CHMIEL, YUH-PYNG SHER, JEREMY CHEN, PAN-CHYR YANG, YIN CHEN, REEN WU
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Development of the high-density DNA microarray technique permits the analysis of thousands of genes simultaneously for their differential expression patterns in various biological processes. Through clustering analysis and pattern recognition, the significance of differentially expressed genes can be recognized and correlated with biological events that may take place inside the cell and tissue. With this notion in mind, high-density DNA microarray nylon membrane with colorimetry detection was used to profile the expression of smoke- and hydrogen peroxide-inducible genes in a human bronchial epithelial cell line, HBE1. On the basis of the time course of expression, at least three phases of change in gene expression could be recognized. The first phase is an immediate event in response to oxidant injury. This phase includes induction of the bcl-2 and mdm-2 genes, which are involved in the regulation of apoptosis, and the mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) gene, that functions as a regulator of various mitogen-activated protein kinase activities. The second phase, usually 5 h later, includes the induction of various stress proteins and ubiquitin, which are important in providing the chaperone mechanism and the turnover of damaged macromolecules. The third phase, which is 5-10 h later, includes the induction of genes that are apparently involved in reducing oxidative stress by metabolizing reactive oxygen species. In this phase, enzymes associated with tissue and cell remodeling are also elevated. These results demonstrate a complex gene expression array by bronchial epithelial cells in response to the insult of oxidants that are relevant to environmental pollutants.
Are fibroblasts involved in joint destruction?
Authors: T Pap
Journal: Annals of the Rheumatic Diseases (2005)

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that primarily affects the joints and results in the progressive destruction of articular structures, particularly cartilage and bone. Notably, the joint destruction is a prominent feature of disease that not only distinguishes RA from other arthritides but also determines its outcome in the majority of affected individuals.

Synovial fibroblasts in the most superficial lining layer of the hyperplastic RA synovium have been assigned an important role in the pathogenesis of RA and associated with key processes leading to the degradation of extracellular matrix. It has been understood that these cells exhibit an altered morphology and are characterised by changes in their behaviour that show certain similarities to tumours. Therefore, the phenotype of these cells has been termed “transformed appearing”, “tumour-like”1 or—reflecting the clear differences with malignancies—“activated”. As part of a cellular network, RA synovial fibroblasts are involved in the destruction of extracellular matrix both by direct mechanisms and through interaction with neighbouring cells such as macrophages. Thus, it has been demonstrated that RA synovial fibroblasts release large amounts of the ligand for the receptor activator of nuclear factor β (RANKL), which mediates the differentiation of bone resorbing osteoclasts from their macrophage precursors.2 Direct degradation of extracellular matrix by RA synovial fibroblasts is mediated through the attachment to cartilage and subsequent release of matrix degrading enzymes, particularly matrix metalloproteinases (MMPs) and cathepsins.3

Although inflammatory cytokines such as tumour necrosis factor α (TNFα) have been demonstrated to stimulate RA synovial fibroblasts to produce such matrix degrading enzymes, the activation of these RA synovial fibroblasts is maintained even in the absence of continuous stimulation by proinflammatory factors. This notion is derived from different in vitro studies as well as from data on the severe combined immunodeficient (SCID) mouse model of rheumatoid …
Genetic advances in sarcomeric cardiomyopathies: state of the art
Authors: C. Y. Ho, P. Charron, P. Richard, F. Girolami, K. Y. Van Spaendonck-Zwarts, Y. Pinto
Journal: Cardiovascular Research (2015)

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine.
COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker
Authors: R Hesselstrand, A Kassner, D Heinegard, T Saxne
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> Cartilage oligomeric matrix protein (COMP), primarily found in cartilage, is thought to be an important regulator of assembly and maintenance of the fibrillar collagen I and II networks. Recently, COMP was shown to be produced by skin fibroblasts from patients with systemic sclerosis (SSc, or scleroderma). The purpose of this study was to examine whether COMP is released from skin to serum in patients with SSc, and may serve as indicator of activity of skin involvement. <h3>Methods:</h3> Serum COMP levels were measured by enzyme linked immunosorbent assay in patients with SSc whose skin involvement was assessed with the modified Rodnan skin score (mRss) and high frequency ultrasound. The presence of COMP in skin biopsies was assessed by Western blot using a monoclonal antibody specific for the very C-terminal end of human COMP. <h3>Results:</h3> Serum COMP correlated to skin involvement as measured by the mRss (n = 70; r<sub>S</sub> = 0.60; p&lt;0.001), to skin thickness measured by ultrasound (n = 88; r<sub>S</sub> = 0.55; p&lt;0.001) and inversely to skin echogenicity measured by ultrasound (n = 88; r<sub>S</sub> = −0.40; p&lt;0.001). In 70 patients followed longitudinally there was a correlation between changes in serum COMP (n = 307) and changes in mRss (r<sub>S</sub> = 0.35; p = 0.008). In individual patients monitored with repeated measurements, serum COMP changes closely paralleled changes in mRss. A C-terminal COMP fragment, with an apparent molecular mass of 56 kDa, was identified in SSc skin biopsies, while no COMP reactivity was detected in normal skin. <h3>Conclusion:</h3> The high turnover of COMP in SSc skin suggests a pathophysiological role. Serum COMP shows promise as a new biomarker in SSc.
Opioid Prescribing: A Systematic Review and Critical Appraisal of Guidelines for Chronic Pain
Authors: Teryl K. Nuckols, Laura Anderson, Ioana Popescu, Allison L. Diamant, Brian Doyle, Paul Di Capua, Roger Chou
Journal: Annals of Internal Medicine (2013)

Background: Deaths due to prescription opioid overdoses have increased dramatically. High-quality guidelines could help clinicians mitigate risks associated with opioid therapy. Purpose: To evaluate the quality and content of guidelines on the use of opioids for chronic pain. Data Sources: MEDLINE, National Guideline Clearinghouse, specialty society Web sites, and international guideline clearinghouses (searched in July 2013). Study Selection: Guidelines published between January 2007 and July 2013 addressing the use of opioids for chronic pain in adults were selected. Guidelines on specific settings, populations, and conditions were excluded. Data Extraction: Guidelines and associated systematic reviews were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument and A Measurement Tool to Assess Systematic Reviews (AMSTAR), respectively, and recommendations for mitigating opioid-related risks were compared. Data Synthesis: Thirteen guidelines met selection criteria. Overall AGREE II scores were 3.00 to 6.20 (on a scale of 1 to 7). The AMSTAR ratings were poor to fair for 10 guidelines. Two received high AGREE II and AMSTAR scores. Most guidelines recommend that clinicians avoid doses greater than 90 to 200 mg of morphine equivalents per day, have additional knowledge to prescribe methadone, recognize risks of fentanyl patches, titrate cautiously, and reduce doses by at least 25% to 50% when switching opioids. Guidelines also agree that opioid risk assessment tools, written treatment agreements, and urine drug testing can mitigate risks. Most recommendations are supported by observational data or expert consensus. Limitation: Exclusion of non–English-language guidelines and reliance on published information. Conclusion: Despite limited evidence and variable development methods, recent guidelines on chronic pain agree on several opioid risk mitigation strategies, including upper dosing thresholds; cautions with certain medications; attention to drug–drug and drug–disease interactions; and use of risk assessment tools, treatment agreements, and urine drug testing. Future research should directly examine the effectiveness of opioid risk mitigation strategies. Primary Funding Source: California Department of Industrial Relations and California Commission on Health and Safety and Workers’ Compensation.
Age-Related Differences in the Frequency of Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents
Authors: Anne Hekkala, Antti Reunanen, Matti Koski, Mikael Knip, Riitta Veijola
Journal: Diabetes Care (2010)

OBJECTIVE We studied the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in children in Finland. RESEARCH DESIGN AND METHODS From 2002 to 2005, data on virtually all children &amp;lt;15 years of age diagnosed with type 1 diabetes (n = 1,656) in Finland were collected. RESULTS DKA was present in 19.4% of the case subjects, and 4.3% had severe DKA. In children aged 0–4, 5–9, and 10–14 years, DKA was present in 16.5, 14.8, and 26.4%, respectively (P &amp;lt; 0.001). Severe DKA occurred in 3.7, 3.1, and 5.9%, respectively (P = 0.048). DKA was present in 30.1% and severe DKA in 7.8% of children aged &amp;lt;2 years. CONCLUSION The overall frequency of DKA in children is low in Finland at diagnosis of type 1 diabetes. However, both children &amp;lt;2 years of age and adolescents aged 10–14 years are at increased risk of DKA.
Proteolytic Cleavage of CD25, the α Subunit of the Human T Cell Interleukin 2 Receptor, by Der p 1, a Major Mite Allergen with Cysteine Protease Activity
Authors: Oliver Schulz, Herb F. Sewell, Farouk Shakib
Journal: The Journal of Experimental Medicine (1998)

Recent reports have indicated that the cysteine protease activity of Der p 1 may play a significant role in its ability to elicit IgE antibody responses, mainly through cleavage of membrane CD23 on B cells and interleukin (IL)-4 synthesis and secretion from mast cells and basophils. Here we demonstrate for the first time that Der p 1 also cleaves the alpha subunit of the IL-2 receptor (IL-2R or CD25) from the surface of human peripheral blood T cells and, as a result, these cells show markedly diminished proliferation and interferon gamma secretion in response to potent stimulation by anti-CD3 antibody. Given that the IL-2R is pivotal for the propagation of Th1 cells, its cleavage by Der p 1 may consequently bias the immune response towards Th2 cells, thereby creating an allergic microenvironment.
<i>Solute carrier family 2 member 1</i>is involved in the development of nonalcoholic fatty liver disease
Authors: Mercedes Vazquez-Chantada, Aintzane Gonzalez-Lahera, Ibon Martinez-Arranz, Carmelo Garcia-Monzon, Manuela M. Regueiro, Juan L. Garcia-Rodriguez, Karin A. Schlangen, Iñaki Mendibil, Naiara Rodriguez-Ezpeleta, Juan J. Lozano, Karina Banasik, Johanne M. Justesen, Torben Joergensen, Daniel R. Witte, Torsten Lauritzen, Torben Hansen, Oluf Pedersen, Nicolas Veyrie, Karine Clement, Joan Tordjman, Albert Tran, Yannik Le Marchand-Brustel, Xabier Buque, Patricia Aspichueta, Jose J. Echevarria-Uraga, Antonio Martin-Duce, Joan Caballeria, Philippe Gual, Azucena Castro, Jose M. Mato, Maria L. Martinez-Chantar, Ana M. Aransay
Journal: Hepatology (2012)

Susceptibility to develop nonalcoholic fatty liver disease (NAFLD) has genetic bases, but the associated variants are uncertain. The aim of the present study was to identify genetic variants that could help to prognose and further understand the genetics and development of NAFLD. Allele frequencies of 3,072 single-nucleotide polymorphisms (SNPs) in 92 genes were characterized in 69 NAFLD patients and 217 healthy individuals. The markers that showed significant allele-frequency differences in the pilot groups were subsequently studied in 451 NAFLD patients and 304 healthy controls. Besides this, 4,414 type 2 diabetes mellitus (T2DM) cases and 4,567 controls were genotyped. Liver expression of the associated gene was measured and the effect of its potential role was studied by silencing the gene in vitro. Whole genome expression, oxidative stress (OS), and the consequences of oleic acid (OA)-enriched medium on lipid accumulation in siSLC2A1-THLE2 cells were studied by gene-expression analysis, dihydroethidium staining, BODIPY, and quantification of intracellular triglyceride content, respectively. Several SNPs of SLC2A1 (solute carrier family 2 [facilitated glucose transporter] member 1) showed association with NAFLD, but not with T2DM, being the haplotype containing the minor allele of SLC2A1 sequence related to the susceptibility to develop NAFLD. Gene-expression analysis demonstrated a significant down-regulation of SLC2A1 in NAFLD livers. Enrichment functional analyses of transcriptome profiles drove us to demonstrate that in vitro silencing of SLC2A1 induces an increased OS activity and a higher lipid accumulation under OA treatment.Genetic variants of SLC2A1 are associated with NAFLD, and in vitro down-regulation of this gene promotes lipid accumulation. Moreover, the oxidative response detected in siSLC2A1-THLE2 cells corroborated the antioxidant properties previously related to this gene and linked the most representative clinical characteristics of NAFLD patients: oxidative injury and increased lipid storage.