tbuckley/cabot-search huggingface dataset:
Pericytes Promote Malignant Ovarian Cancer Progression in Mice and Predict Poor Prognosis in Serous Ovarian Cancer Patients
Authors: Devbarna Sinha, Lynn Chong, Joshy George, Holger Schlüter, Susann Mönchgesang, Stuart Mills, Jason Li, Christopher Parish, David Bowtell, Pritinder Kaur
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The aim of this study was to investigate the role of pericytes in regulating malignant ovarian cancer progression. Experimental Design: The pericyte mRNA signature was used to interrogate ovarian cancer patient datasets to determine its prognostic value for recurrence and mortality. Xenograft models of ovarian cancer were used to determine if co-injection with pericytes affected tumor growth rate and metastasis, whereas co-culture models were utilized to investigate the direct effect of pericytes on ovarian cancer cells. Pericyte markers were used to stain patient tissue samples to ascertain their use in prognosis. Results: Interrogation of two serous ovarian cancer patient datasets [the Australian Ovarian Cancer Study, n = 215; and the NCI TCGA (The Cancer Genome Atlas), n = 408] showed that a high pericyte score is highly predictive for poor patient prognosis. Co-injection of ovarian cancer (OVCAR-5 &amp; -8) cells with pericytes in a xenograft model resulted in accelerated ovarian tumor growth, and aggressive metastases, without altering tumor vasculature. Pericyte co-culture in vitro promoted ovarian cancer cell proliferation and invasion. High αSMA protein levels in patient tissue microarrays were correlated with more aggressive disease and earlier recurrence. Conclusions: High pericyte score provides the best means to date of identifying patients with ovarian cancer at high risk of rapid relapse and mortality (mean progression-free survival time &amp;lt; 9 months). The stroma contains rare yet extremely potent locally resident mesenchymal stem cells—a subset of “cancer-associated fibroblasts” that promote aggressive tumor growth and metastatic dissemination, underlying the prognostic capacity of a high pericyte score to strongly predict earlier relapse and mortality. Clin Cancer Res; 22(7); 1813–24. ©2015 AACR.
Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia.
Authors: L Lennard, J S Lilleyman
Journal: Journal of Clinical Oncology (1989)

Intracellular thioguanine nucleotides (6-TGN) are the major cytotoxic metabolites of mercaptopurine (6-MP). Red blood cell (RBC) 6-TGN concentrations were measured in a group of 120 consecutive children with lymphoblastic leukemia (ALL) to assess interpatient variability and its clinical importance. Assays were performed after at least 2 months 6-MP maintanance chemotherapy and a minimum 7 days unattenuated protocol dose of 75 mg/m2. Observed 6-TGN concentrations ranged from 126 to 832 pmol/8 x 10(8) RBCs (median, 275). There was a correlation between 6-TGN and neutropenia 14 days postassay (rs = .51; P less than .0005), and an inverse correlation between 6-TGN and the length of time uninterrupted full protocol dose was tolerated without neutropenia (rs = -.3; P less than .01). After a median follow-up of 49 months, 19 children had relapsed, of whom 17 (89%) had 6-TGN concentrations below the group median (log-rank chi 2 = 11.9; P less than .001). Multivariate analysis using Cox's proportional hazards regression showed the 6-TGN effect on disease control to be independent of diagnostic WBC count, sex, age, immunological cell type, French-American-British (FAB) type, variation in other antineoplastic therapy, and duration of remission at the time of 6-TGN assay. Children with ALL taking the same dose of 6-MP show great variability in its measurable cytotoxic effect, and this variability is apparently important in predicting treatment outcome.
A bleeding umbilical mass
Authors: Francesco Guerra, Fabio Pulighe, Riccardo Sacchetti, Stefano Serra, Carlo De Nisco
Journal: Gut (2015)

A 57-year-old man with a 3-year history of diabetes was referred to our surgical department for evaluation of a bleeding lesion in the umbilicus (figure 1). The patient reported having been evaluated 4 months before and scheduled for umbilical hernia repair. At presentation, the patient reported vague back pain, whereas he denied fever, nausea or vomiting. Upon physical examination, the abdomen was soft, with normal bowel sounds. There was an obvious, …
Lamination Speeds the Functional Development of Visual Circuits
Authors: Nikolas Nikolaou, Martin P. Meyer
Journal: Neuron (2015)

A common feature of the brain is the arrangement of synapses in layers. To examine the significance of this organizational feature, we studied the functional development of direction-selective (DS) circuits in the tectum of astray mutant zebrafish in which lamination of retinal ganglion cell (RGC) axons is lost. We show that although never laminar, the tuning of DS-RGC axons targeting the mutant tectum is normal. Analysis of mutant tectal neurons at late developmental stages reveals that directional tuning is indistinguishable from wild-type larvae. Furthermore, we show that structural plasticity of tectal dendrites and RGC axons compensates for the loss of lamination, establishing connectivity between DS-RGCs and their normal tectal targets. However, tectal direction selectivity is severely perturbed at earlier developmental stages. Thus, the formation of synaptic laminae is ultimately dispensable for the correct wiring of direction-selective tectal circuits, but it is crucial for the rapid assembly of these networks.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJkYjlhOTA0MmUzYTYxMWVhYzcyODUyNTlhYjlhYjIyMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4Mjk2NDg2fQ.eHrSinLiiBDcPofKGnG3tJWuhlRkN2hBVp6y2eY8QHrDLamyZutpmb68VWa6W55YGLGrQXpEApte5auboA6ZVCsoRKOTsnIHk7i8cylr9ZE7-7E_sLfXQdsZe6e_6rRJ6HPvL_MzEB31VPstuSt70jBRFTW33_dyDA9cF_dU9aarAIQecUdaiO7jqiEICDLZdzqNS9AtyRR9ZUyvdZPyJoOuJP1HaIpm-OwF6qnIBdzjjaiWAUBdtwEwPdij3Dke7L9Jg5EU068njXCSSbAynMTyUIrA9VVP0bB88dnYZ5sYtpaht7hHD6MLR1BPhKOGJJXMgtC_bew0bWobJWZuEQ(mp4, (23.7 MB) Download video
Superficial bladder cancer: the primacy of grade in the development of invasive disease.
Authors: F M Torti, B L Lum, D Aston, N MacKenzie, M Faysel, L D Shortliffe, F Freiha
Journal: Journal of Clinical Oncology (1987)

Tumor characteristics thought to predict for development of deep muscle invasion after resection of superficial bladder cancer were retrospectively analyzed in 252 patients with transitional cell carcinoma of the bladder at Stanford University Medical Center. Stage 0 patients accounted for 190 of the patient population (75.5%), while stage A and B1 comprised 51 (20%) and 11 (4.5%), respectively. The median follow-up time was 62 months. Forty-three patients subsequently developed deep muscle invasion; these included 24 (12.6%), 14 (27.5%), and 5 (45.5%) of stage 0, A, and B1 patients (P = .002), or 15 (10%), 15 (9%), and 13 (33%) of grade 1, 2, and 3 tumors (P = .001), respectively. When analyzed by univariate logistic regression, grade (P = .0001) and stage (P = .0118) were significant predictors for invasive disease. Site of tumor and number of tumors at presentation were not significant factors for invasion deep into the bladder wall. When multiple logistic regression was performed, only grade remained as a significant tumor variable to predict for invasive disease (P less than .0091). Risk of invasive disease did not appear to increase with increasing number of recurrences, remaining at approximately an 11% invasion rate through 12 recurrences. In this analysis, grade was the most significant tumor variable in superficial bladder cancer predicting for the development of invasive carcinoma. Future clinical trials for definitive or adjuvant therapy of this disease must stratify for this variable.
Antineoplastic Agents from Plants
Authors: M E Wall, M C Wani
Journal: The Annual Review of Pharmacology and Toxicology (1977)

Since at least 1500 Be plants and plant extracts have been recognized as having anticancer activities (1). Surveys by Hartwell (2, 3) listed at least 3000 species so used. However the rational, organized study of plants as sources of potential an­ tineoplastic agents probably commenced with the pioneering studies of Hartwell et al (4-8) during the period 1947-1953 in which for the first time pure plant constit­ uents were isolated, characterized, and associated with the antitumor activity of the crude plant extract.! This review presents a critical appraisal of the current status of plant antineoplas­ tic agents, with particular emphasis on chemical structure and the significant fea­ tures (where known) that are required for antitumor activity. This review deals only with plant antineoplastic agents of high activity against mouse leukemia and mouse and rat solid tumors as defined by the National Cancer Institute (9). All ofthe plant antitumor agents covered have excellent antitumor activity in one or more rodent tumor or leukemia systems combined with reasonable therapeutic indices so that the agents are either in clinical testing or scheduled for such studies. As a consequence, many substances with marginal activity or with high toxicity are not included in this review. Material covered in earlier reviews (1, 10) is not discussed unless additional information has become available since the time of the previous review.
Residual abdominal masses in aggressive non-Hodgkin's lymphoma after combination chemotherapy: significance and management.
Authors: A Surbone, D L Longo, V T DeVita, D C Ihde, P L Duffey, E S Jaffe, D Solomon, S M Hubbard, R C Young
Journal: Journal of Clinical Oncology (1988)

When patients with aggressive lymphoma present with intraabdominal disease, a stable residual mass is frequently detected radiographically at the time of the clinical complete remission. To discern the optimal management for this clinical problem, we reviewed 241 patients with aggressive lymphoma treated at the National Cancer Institute (NCI) from 1977 to 1986. Seventy-two/241 patients (30%) had an abdominal mass at diagnosis and 29/72 (40%) were left with a radiographically detectable residual mass at clinical complete remission. The likelihood of a residual mass was much higher for patients with bulky disease (P2 less than .0003) (two-tailed test [P2]). Twenty-nine patients had radiologically stable residual masses after therapy, and of 22 (76%) with pathologic evaluations, 21 had negative specimens (95%) and one was positive (5%). None of the patients with negative pathologic evaluation has relapsed in the abdominal site (median follow-up, 31 months). Seven patients were observed clinically without laparotomy: five are alive, without evidence of disease, at 2 to 9 years; two relapsed with disseminated disease within 2 months of chemotherapy. Initial tumor size and size of the residual mass did not correlate with residual disease, since residual masses identified by radiographic examination did not usually harbor viable lymphoma cells. Aspiration cytology was negative for residual tumor in 15/16 cases. One negative result was not confirmed at laparotomy, presumably due to sampling error. The one positive aspiration was followed by a negative laparotomy, possibly due to subsequent tumor necrosis. Restaging laparotomy has a low yield. In most patients with aggressive lymphoma who have otherwise completely responded to carefully administered full-dose combination chemotherapy, stable residual abdominal masses can be closely followed clinically without surgical exploration.
Evaluating an Elevated Screening PSA Test
Authors: Michael J. Barry, Julia H. Hayes
Journal: JAMA (2015)

Test Characteristics The operating characteristics of the PSA test for prostate cancer screening depend on the definition of disease. The Prostate Cancer Prevention Trial (PCPT), a large study that obtained biopsies on men regardless of PSA level, provides the most relevant data. Twenty-two percent of PCPT participants had prostate cancer, and approximately onequarter of these men had a Gleason score of at least 7.1 Men at average risk have an approximate 3% probability of dying of prostate cancer.2 At a PSA threshold greater than 4.0 ng/mL, PSAwas 20.5% sensitive and 93.8% specific when any histologic prostate cancer was considered disease.1 However, cancersthatarewell-differentiatedare indolentandgenerallydonotneed early detection. If only cancerswith aGleason score of at least 7 are considereddisease, then sensitivity increases to40.4%, and specificitywouldbe90.0%.ThePCPT investigatorshavepublisheda risk calculator thatuses race/ethnicity, age,PSA level, familyhistory,DRE result, and history of prostate biopsy to estimate the probability of high-grade(Gleason 7)andlow-grade(Gleason<7)prostatecancer.3 There is no absolute threshold for considering a biopsy based on a specific PSA level or the estimated risk of prostate cancer from the calculator. In the European Randomized Study of Prostate Cancer Screening, the trial that found a significant reduction in prostate cancer mortality with screening, a testing frequency of every 4 years and a biopsy threshold of at least 3.0 ng/mL was generally used.4 Modeling studies suggest that with biennial testing, a biopsy threshold of greater than 4.0 ng/mL is associated with a slightly higher probability of prostate cancer death than lower thresholds but with a reduced risk of false-positive results.5 Another reasonable approach is to use the estimated probabilities from the PCPT calculator in a shared decision-making process with men facing the biopsy decision.6 In the Prostate Cancer Intervention vs Observation Trial, a prespecified subgroup analysis suggested radical prostatectomy was associated with lower mortality among participants with a baseline PSA level of greater than 10 ng/mL when compared with men with lower PSA levels. This finding implies the PSA level at which prostate cancers (those needing and amenable to curative treatment) progress beyond curability may be higher than the commonly used threshold of greater than 4 ng/mL.7 HOWDOYOU INTERPRETTHESERESULTS?
Abstract 2491: Risk Factors in First Presentation Acute Coronary Syndromes (ACS): How do we Move From Population to Individualized Risk Prediction?
Authors: Fadi A Saab, Apurva Motivala, Hitinder Gurm, Eva Kline-Rogers, Daniel G. Montgomery, Melvyn Rubenfire, Jim Froehlich, Kim A Eagle
Journal: Circulation (2006)

Background: Patients with acute coronary syndromes (ACS) have a poor short and long-term prognosis. Identifying and treating persons with classic coronary risk factors represents the best opportunity to prevent ACS. Hypothesis: We sought to examine the presence of coronary risk factors in contemporary patients presenting with an ACS and no known CAD. Methods: A prospective cohort study was conducted in 3171 consecutive patients admitted to the University of Michigan between 1999 and 2004 with the diagnosis of ACS. Of these, 941 patients (30%) had a first ACS and no history of CAD. Coronary risk factors were defined as: age >65 years, LDL >130, low HDL (<40 in men, <50 in women), smoking (current or former), diabetes, hypertension, renal failure, family history of CAD and dyslipidemia (diagnosed hyperlipidemia or patients on therapy). Results: Patients were divided into groups by number and combinations of risk factors (1–7)(see figure). Only 2.5% of patients had no coronary risk factors. The most prevalen...
The genetic association of<i>RUNX3</i>with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression
Authors: Matteo Vecellio, Amity R Roberts, Carla J Cohen, Adrian Cortes, Julian C Knight, Paul Bowness, B Paul Wordsworth
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> To identify the functional basis for the genetic association of single nucleotide polymorphisms (SNP), upstream of the <i>RUNX3</i> promoter, with ankylosing spondylitis (AS). <h3>Methods</h3> We performed conditional analysis of genetic association data and used ENCODE data on chromatin remodelling and transcription factor (TF) binding sites to identify the primary AS-associated regulatory SNP in the <i>RUNX3</i> region. The functional effects of this SNP were tested in luciferase reporter assays. Its effects on TF binding were investigated by electrophoretic mobility gel shift assays and chromatin immunoprecipitation. <i>RUNX3</i> mRNA levels were compared in primary CD8+ T cells of AS risk and protective genotypes by real-time PCR. <h3>Results</h3> The association of the <i>RUNX3</i> SNP <i>rs4648889</i> with AS (p&lt;7.6×10<sup>−14</sup>) was robust to conditioning on all other SNPs in this region. We identified a 2 kb putative regulatory element, upstream of <i>RUNX3</i>, containing <i>rs4648889.</i> In reporter gene constructs, the protective <i>rs4648889</i> 'G' allele increased luciferase activity ninefold but significantly less activity (4.3-fold) was seen with the AS risk 'A' allele (p≤0.01). The binding of Jurkat or CD8+ T-cell nuclear extracts to the risk allele was decreased and IRF4 recruitment was reduced. The AS-risk allele also affected H3K4Me1 histone methylation and associated with an allele-specific reduction in <i>RUNX3</i> mRNA (p&lt;0.05). <h3>Conclusion</h3> We identified a regulatory region upstream of <i>RUNX3</i> that is modulated by <i>rs4648889</i>. The risk allele decreases TF binding (including IRF4) and reduces reporter activity and <i>RUNX3</i> expression. These findings may have important implications for understanding the role of T cells and other immune cells in AS.
The Mechanism of Action of Vitamin K
Authors: Paul Dowd, Seung-Wook Ham, Sriram Naganathan, Roger Hershline
Journal: Annual Review of Nutrition (1995)

Vitamin K is the blood-clotting vitamin. The mechanism of action of vitamin K is discussed in terms of a new carbanion model that mimics the proton abstraction from the gamma position of protein-bound glutamate. This is the essential step leading to carboxylation and activation of the blood-clotting proteins. The model comprises an oxygenation that is coupled to carbon-carbon bond formation, as is the oxygenation of vitamin K hydroquinone to vitamin K oxide. The model hypothesis is also supported by the mechanism of inhibition of the carboxylase by HCN, which acts as an acid-base inhibitor rather than a metal-complexing inhibitor. The new model postulates a dioxetane intermediate that explains the presence of a second atom of 18O (from 18O2) incorporated into vitamin K oxide in the course of the enzymatic carboxylation. Finally, the chemistry developed here has been used to define the active site of vitamin K hydroquinone as the carbon-carbon bond adjacent to the methyl group.
The Role of the Adrenal Cortex in Fluid and Electrolyte Metabolism
Authors: F. T. G. Prunty, H. E. M. Kay, G. d. J. Lee, R. R. McSwiney
Journal: BMJ (1953)

1.-Kepler te N represents urine 3, and 4 represent cortone is to increase sodium and chloride reabsorption, E ROLE OF THIE since low serum sodium levels are rapidly elevated and CORTEX IN FLUID AND excretion of these ions is decreased.Whether there is a direct effect on water reabsorption or whether this is secon- OLYTE METABOLISM* dary to the electrolyte change is uncertain.The work of BY Verney shows that under normal conditions the posterior pituitary is a rapid reactor to water losses and seems to be PRUNTY, M.D., F.R.C.P.stimulated by hypertonicit-of the plasma.In Addison's
The neuroimmune guidance cue netrin‐1 controls resolution programs and promotes liver regeneration
Authors: Martin Schlegel, David Köhler, Andreas Körner, Tiago Granja, Andreas Straub, Martin Giera, Valbona Mirakaj
Journal: Hepatology (2015)

Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti‐inflammatory properties of the axonal guidance cue netrin‐1 were reported. Here, we demonstrate that netrin‐1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of netrin‐1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic netrin‐1 deficiency (Ntn1 +/− ) or wild‐type C57BL/6 treated with exogenous netrin‐1 to examine the endogenous and therapeutically administered impact of netrin‐1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of netrin‐1 transcript and protein in murine liver tissue. Subsequent studies in netrin‐1‐deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic‐specific injury enzymes. Conversely, mice treated with exogenous netrin‐1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in netrin‐1‐mediated protection during hepatic I/R injury. Conclusion: The present study indicates a previously unrecognized role for netrin‐1 in liver protection and its contribution to tissue homeostasis and regeneration. (H epatology 2016;63:1689‐1705)
Lung inhomogeneities, inflation and [<sup>18</sup>F]2-fluoro-2-deoxy-D-glucose uptake rate in acute respiratory distress syndrome
Authors: Massimo Cressoni, Davide Chiumello, Chiara Chiurazzi, Matteo Brioni, Ilaria Algieri, Miriam Gotti, Klodiana Nikolla, Dario Massari, Antonio Cammaroto, Andrea Colombo, Paolo Cadringher, Eleonora Carlesso, Riccardo Benti, Rosangela Casati, Felicia Zito, Luciano Gattinoni
Journal: European Respiratory Journal (2015)

The aim of the study was to determine the size and location of homogeneous inflamed/noninflamed and inhomogeneous inflamed/noninflamed lung compartments and their association with acute respiratory distress syndrome (ARDS) severity.In total, 20 ARDS patients underwent 5 and 45 cmH2O computed tomography (CT) scans to measure lung recruitability. [(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake and lung inhomogeneities were quantified with a positron emission tomography-CT scan at 10 cmH2O. We defined four compartments with normal/abnormal [(18)F]FDG uptake and lung homogeneity.The homogeneous compartment with normal [(18)F]FDG uptake was primarily composed of well-inflated tissue (80±16%), double-sized in nondependent lung (32±27% versus 16±17%, p<0.0001) and decreased in size from mild, moderate to severe ARDS (33±14%, 26±20% and 5±9% of the total lung volume, respectively, p=0.05). The homogeneous compartment with high [(18)F]FDG uptake was similarly distributed between the dependent and nondependent lung. The inhomogeneous compartment with normal [(18)F]FDG uptake represented 4% of the lung volume. The inhomogeneous compartment with high [(18)F]FDG uptake was preferentially located in the dependent lung (21±10% versus 12±10%, p<0.0001), mostly at the open/closed interfaces and related to recruitability (r(2)=0.53, p<0.001).The homogeneous lung compartment with normal inflation and [(18)F]FDG uptake decreases with ARDS severity, while the inhomogeneous poorly/not inflated compartment increases. Most of the lung inhomogeneities are inflamed. A minor fraction of healthy tissue remains in severe ARDS.
Synaptic Regulation of Mesocorticolimbic Dopamine Neurons
Authors: F J White
Journal: Annual Review of Neuroscience (1996)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More