tbuckley/cabot-search huggingface dataset:
Abstract 4947: Homeobox gene <i>HOPX</i> is epigenetically silenced cancer-specifically in colorectal cancer and predicts poor prognosis in stage III colorectal cancer
Authors: Hiroshi Katoh, Keishi Yamashita, Akira Ooki, David Sidransky, Masahiko Watanabe
Journal: Cancer Research (2010)

Abstract (Background) Colorectal cancer (CRC) is the second most prevalent cancer, and chemotherapy has dramatically improved prognostic outcome of CRC patients over the past several decades. Nonetheless, CRC remains the fourth leading cause of cancer death world-wide, and stage III patients have a high potential for recurrence even after curative surgery. Homeodomain only protein X (HOPX) is a recently identified homeobox gene whose loss of expression has been reported for several types of cancer by promoter DNA CpG islands methylation, but there is no information in CRC. (Materials and Methods) HOPX is encoding 3 spliced transcript variants, among which the promoter of the isoform b alone (promoter B) harbors CpG islands. We evaluated the impact of its methylation status of promoter B of HOPX gene in CRC. We evaluated 9 CRC cell lines and primary tumor tissue of 245 CRC patients. The methylation status was evaluated by bisulfate sequencing and quantitative methylation specific TaqMan real-time PCR (quantitative-MSP). (Result) HOPX b mRNA was silenced or remarkably reduced in expression in 8 of 9 CRC cell lines tested. And the expression was robustly restored by treatment with demethylating agents such as 5-aza-2′-deoxycitidine and/or trichostatin A. On quantitative-MSP, HOPX promoter B hypermethylation was found in 56.6% (56/99) of primary tumor tissues and 0% (0/98) of corresponding normal tissues, if cut-off value was set to 2.89) (specificity reached 100.0%). Such cancer-specific methylation was not associated with prognostic factors representing TNM stage factors in the 100 initial leaning sets. However, patients with HOPX promoter B hypermethylation showed significantly worse prognosis than hypomethylated patients (P=0.03), only in 170 stage III patients which have a high potential for recurrence even after curative surgery. And this tendency was also observed even in dissociative analysis of UICC N factor (P=0.01 in N1, P=0.08 in N2). (Conclusion) Our study indicates that transcriptional silencing of HOPX predominantly results from HOPX promoter B methylation, which is a highly specific marker for CRC and also have a potential as a biomarker for tumor malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4947.
Abstract 2710: SRC/STAT related parameters might predict for prognosis and response to targeted treatments in squamous cell carcinomas of the head and neck (SCCHN)
Authors: V. Kotoula, S. Lampaki, D. Televantou, A. Psyrri, D. Pectasides, X. Mavropoulou, D. Misailidou, K. N. Syrigos, G. Fountzilas
Journal: Cancer Research (2010)

Abstract The anti-EGFR antibody cetuximab (Erbitux®, CTX) has been introduced into clinical practice for the treatment of SCCHN, as yet with modest effectiveness. Src family targeting agents have shown anti-growth activity in SCCHN preclinical models and are currently considered for further exploration in the same tumor system. In this study we investigated the expression and activation of SRC/STAT pathway components in SCCHN in order to assess how they are related to already in use and upcoming, targeted treatment modalities. Relative expression of SRC, STATs 1,3,5 and related genes was assessed with real time PCR in tumor tissue extracts from SCCHN patients treated with combined radiotherapy and cetuximab-based regimens (RT-CTX). Stat and Akt/PKB protein activation were assessed with immunohistochemistry. SCCHNs always expressed SRC, STAT1, STAT3 and ANXA1 mRNA, variably high levels of IGFBP2 and STAT5A and mostly low STAT5B, PIAS3 and MSN. Stat1, Stat3 and Stat5 proteins were usually found activated in neoplastic nuclei (70.4%, 85.7% and 70.8%, respectively), although not correlating to the respective STAT mRNA expression levels. Activated Stat3 and Stat5 were associated with each other (p=0.017) and with relatively high CAV1 (pStat3=0.0079; pStat5=0.0107) and MSN (pStat3=0.0463; pStat5=0.0077), as well as with relatively low IGFBP2 expression (pStat3=0.0181; pStat5=0.0328). Akt was phosphorylated at Thr308 in the majority of SCCHN (86.7%) and less so at Ser473 (41.9%) in association with low STAT1 mRNA expression (p=0.0316). All patients with very high expression (upper quartile) of STAT5A and/or EPHA2 experienced a complete response upon RT-CTX treatment (p&amp;lt;0.0001), while all patients without activated Stat1 were also responders (p=0.009). Few tumors (3 of 31, 9.7%) expressed relatively high ANXA1/CAV1/EPHA2 and low IGFBP2, a profile previously proposed to predict response to dasatinib. Very high expression of ANXA1 (an anti-inflammatory molecule possibly associated with chemoradiation resistance) was associated with poor overall (p=0.0009) and progression-free survival (p=0.0004) in this cohort of SCCHN patients. In conclusion, the proposed signature for predicting response to dasatinib in solid tumors is seldom observed in SCCHN. Stat3 and Stat5 activation is common and seems to occur in the anti-oncogenic setting in SCCHN, where overexpression of STAT5A and EPHA2 may predict for response to RT-CTX treatment. If validated in larger cohorts, these data may be applied for assessing SCCHN patient treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2710.
Lagging Immunity of Our Children
Authors: Dorothy M. Horstmann
Journal: New England Journal of Medicine (1971)

The recovery of Type 2 poliovirus from an infant and two close contacts, reported in this week's correspondence by Lamb and Feldman (page 1435), highlights a growing problem in the United States. Despite the availability of effective vaccines, and the remarkable success that has been achieved in virtually eliminating paralytic poliomyelitis from large geographic areas by their use, there are warning signals of potential danger ahead. This relates to the evidence that although circulation of wild polioviruses has been greatly reduced, these agents are still lurking about, and if a sizable number of susceptible persons were allowed to build up, . . .
P124 Effusion Size on the Chest Radiograph at Day 7 Post-Pleural Drainage is a Good Predictor of Size at 3 Months, Regardless of Initial Intrapleural Therapy
Authors: RJ Hallifax, M Nagendran, M Maruthappu, A Manuel, JM Wrightson, NA Maskell, HE Davies, NM Rahman
Journal: Thorax (2012)

<h3>Introduction</h3> Drainage of infection pleural fluid is essential in improving patient outcomes. The MIST-2 Trial (NEJM 2011) demonstrated intrapleural tissue plasminogen activator (t-PA) and DNase therapy improves drainage in patients with pleural infection from Day 1 to 7 compared to placebo. However, there is no evidence assessing whether this difference is sustained at 3 months. Methodology used in the MIST-2 trial demonstrated that a digital chest radiograph measurement strategy was an effective measurement of pleural fluid volume and correlated closely with computed tomography scanning in estimating effusion size. <h3>Aims</h3> To determine whether intrapleural treatment with t-PA, DNase, or both, showed a sustained significant difference in effusion size at 3 months. To assess predictors of residual pleural shadowing 3 months post treatment. <h3>Methods</h3> 132/193 (68%) patients in the MIST-2 trial had assessable chest radiographs at 3 months (remaining patients were lost to follow-up or died). Effusion size was measured as a percentage of the hemithorax occupied on digital radiograph image (JPEG format). Each image was analysed independently by a medical student and respiratory specialist. Where the difference in estimates exceeded 2%, the radiographs were reassessed together to generate consensus. Analysis was blind to treatment arm. <h3>Results</h3> There was no significant difference between placebo and any treatment group in the 3 month radiology outcome. The 3 month effusion size was positively correlated with that at Day 7 (Pearsons 0.27, p=0.003). Neither Day 1 effusion size, nor the difference between Day 1 to 7 was significantly correlated with 3 month outcome. Linear regression analysis demonstrated significant correlation for Day 7 effusion size with 3 months size (p=0.004), but non-significance by treatment arm (p=0.071). <h3>Conclusions</h3> In those that survive and have a chest radiograph at 3 months, there is no difference in the radiological outcome at 3 months between treatment groups on the basis of treatments given, including surgical intervention. However, the appearance at day 7 is significantly correlated with the 3 month chest radiograph. Further statistical modelling of this data is now required to assess the relative contributions of intrapleural interventions and surgery in those that survive to 3 months.
Abstract 3180: Mutation detection in circulating free DNA using mutant-enriched PCR and digital PCR
Authors: Ling-Yuh Huw, Jill Spoerke, Rajesh Patel, Weiqun Liu, Rajiv Raja, Lukas Amler, Garret Hampton, Elizabeth Punnoose, Mark Lackner
Journal: Cancer Research (2011)

Abstract Mutations in oncogenes such as EGFR, KRAS and PIK3CA, have been shown to have profound effects on pathway signaling and tumor growth. These genetic aberrations are potentially valuable predictors for patient stratification and therapeutic responses to targeted therapies directed against these signaling pathways. Here we evaluate the utility of circulating tumor DNA as a “liquid biopsy” for predictive diagnostics and real-time monitoring of disease. A fundamental challenge with this approach is that, due to the low frequency of the mutant tumor DNA in circulation, a highly sensitive assay is required to detect the single base pair alterations. We have designed and investigated several assay formats, including TaqMan and scorpion-ARM assays for mutation detection using a digital PCR platform. We also employed LNA/PNA blockers and thermostable restriction digestion in PCR reaction to enrich the mutant DNA. The combination of the biased amplification and digital PCR dramatically increased mutation detection 10-100 fold. To assess clinical utility of the technology, data on PIK3CA mutation screening of matched patient tumor and plasma samples from a phase I clinical trial will also be reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3180. doi:10.1158/1538-7445.AM2011-3180
Code Red and Blue — Safely Limiting Health Care's GDP Footprint
Authors: Arnold Milstein
Journal: New England Journal of Medicine (2012)

Interview with Dr. Arnold Milstein on learning health systems and their role in reducing health care spending. (00:00)Download U.S. health care value is low, and the gap between health spending growth and growth of the GDP saps economic vitality. Our health care system needs to adopt new work methods, outlined in the Institute of Medicine's vision of a learning health system.
Headliners: Developmental Neurotoxicity: Drug Used to Arrest Preterm Labor Sensitizes the Brain to Neurotoxicants
Authors: Jerry Phelps
Journal: Environmental Health Perspectives (2004)

In a town that devotees call t h e " S o u t h e r n P a r t o f Heaven," the University of North Carolina at Chapel Hill (UNC-CH) is known nationally for its schools of public health, medicine, and pharmacy.These schools are physically just across the street from one another, but they can seem worlds away if their knowledge and resources aren't shared.To bring these researchers together, the Center for Environmental Health and Susceptibility (CEHS) was funded with a $3.78 million, four-year grant from the NIEHS to become one of 22 Environmental Health Sciences Centers. "We have an unusual mix of basic, clinical, and population scientists," says CEHS director James Swenberg, a UNC-CH professor of environmental sciences and engineering."The center's goal is to, by bringing these groups together, expand our vision of environmental health research."Center researchers work to understand the fundamental processes that contribute to chemical toxicity and to combine this knowledge with epidemiology to reduce environmental disease.Increasingly, work at the center focuses on understanding how environmental and genetic determinants of disease work together in populations.And whereas researchers have in the past focused largely on average susceptibility when looking at the distribution of disease among a particular population, CEHS scientists are among those now looking at populations with greater-or lesser-than-average disease susceptibility, Swenberg says.Furthermore, they are trying to help people understand what role their genetic makeup plays in susceptibility.That expanded vision can be seen in the center's recent growth, in April 2004, from three research cores to five.The center also includes four facility cores to offer services such as high-throughput genetic analysis, provision of a variety of biomarkers, and expertise on statistical design and analysis.And the Community Outreach and Education Program (COEP) brings what researchers are learning to the people of North Carolina and beyond.
FRI0303 Validation of eular primary sjögren’s syndrome disease activity and patient indexes
Authors: R. Seror, E. Theander, J. Brun, M. Ramos-Casals, V. valim, T. Dörner, X. Mariette, H. bootsma, A. Tzioufas, R. Solans Laqué, T. Mandl, J.-E. Gottenberg, E. Hachulla, W.-F. Ng, S. Bombardieri, R. Gerli, T. sumida, A. saraux, M. tomsic, R. caporali, R. Priori, K. Moser, A. A. Kruize, C. Vollenweider, P. Ravaud, S. Praprotnik, H. Scofield, G. Valesini, C. Montecucco, A. L. Fauchais, C. Vitali, S. Bowman
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To validate the EULAR scores for assessment of primary Sjögren's Syndrome (SS): the EULAR SS Disease Activity Index (ESSDAI), the EULAR SS Patient Reported Index (ESSPRI). <h3>Methods</h3> Prospective international validation study with 2 visits: baseline and 6 months. At each physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögren's Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Construct validity (using correlations with gold standard), responsiveness (using standardized response mean [SRM]) and reliability (intraclass correlation coefficient [ICC]) were evaluated and compared between each scores. <h3>Results</h3> 395 patients (96% women, mean age 55.4 ± 13.7 years, 79% with anti-SSA and/or anti-SSB antibodies) from 15 countries have been included. At enrollment, 145 (37%) and 251 (64%) had, respectively, current or either current or past systemic manifestations. EULAR scores had higher correlation with gold standard than other scores (ESSDAI with PhGA: rho=0.59; ESSRPI with PGA: rho=0.70). Correlations between patient and systemic scores were very low (rho ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients (SRM= 0.69 to 0.82). Responsiveness of patients scores was low in patient experiencing improvement of their symptoms but was significantly higher for ESSPRI compared to SSI and PROFAD ((SRM=0.37 vs. 0.04 and 0.16; p=0.006 and 0.049 for SRM comparisons). Reliability was assessed in a subgroup of 47 and 62 patients, for systemic and patients scores, respectively. Reliability was very good for all scores (ICC=0.83 to 0.96). <h3>Conclusions</h3> ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores were sensitive to change in patients whose disease activity improves. Patient scores had a small sensitivity to change. However, ESSPRI was significantly better than SSI and PROFAD. The poor correlation between systemic and patients scores confirms that these 2 components are different and should be evaluated separately. <b>Disclosure of Interest</b>: None Declared
Delayed Puberty and Hypogonadism Caused by Mutations in the Follicle-Stimulating Hormone β-Subunit Gene
Authors: Lawrence C. Layman, Eun-Jig Lee, Douglas B. Peak, Anne B. Namnoum, Kenneth V. Vu, Barbara L. van Lingen, Mark R. Gray, Paul G. McDonough, Richard H. Reindollar, J. Larry Jameson
Journal: New England Journal of Medicine (1997)

The pituitary gonadotropins luteinizing hormone and follicle-stimulating hormone (FSH) regulate the production of sex steroids necessary for pubertal development and fertility. Inherited genetic defects that cause hypogonadism have been identified at multiple levels of the hypothalamic–pituitary–gonadal axis.1 They include Kallmann's syndrome, which is caused by mutations in the KAL gene,2 and X-linked adrenal hypoplasia, which is caused by mutations in the DAX-1 gene.3 Both cause deficiency of hypothalamic gonadotropin-releasing hormone, and DAX-1 mutations also cause a defect in the production of gonadotropins by the pituitary.4 A homozygous mutation in the gene for the β-subunit of luteinizing hormone has been reported . . .
Comparison of High-Dose with Low-Dose Subcutaneous Heparin to Prevent Left Ventricular Mural Thrombosis in Patients with Acute Transmural Anterior Myocardial Infarction
Authors: Alexander G.G. Turpie, John G. Robinson, Daniel J. Doyle, Amin S. Mulji, Gregory J. Mishkel, Brian J. Sealey, John A. Cairns, Leslie Skingley, Jack Hirsh, Michael Gent
Journal: New England Journal of Medicine (1989)

We performed a double-blind randomized trial comparing high doses of subcutaneous heparin (12,500 units every 12 hours) with low doses (5000 units every 12 hours) for 10 days in the prevention of left ventricular mural thrombosis in 221 patients with acute anterior myocardial infarction. Left ventricular mural thrombosis was observed by two-dimensional echocardiography on the 10th day after infarction in 10 of 95 patients (11 percent) in the high-dose group and in 28 of 88 patients (32 percent) in the low-dose group (P = 0.0004). One patient in the high-dose group and four in the low-dose group had nonhemorrhagic strokes (P = 0.17). One patient in the low-dose group had a fatal pulmonary embolism. There was no difference in the frequency of hemorrhagic complications, which occurred in six patients in the high-dose group and four in the low-dose group. The mean (±SEM) plasma heparin concentration was 0.18±0.017 U per milliliter in the high-dose group and 0.01 ±0.005 U per milliliter in the low-dose group (P<0.0001). In the high-dose group, the mean plasma heparin concentration was 0.10±0.029 U per milliliter among patients with abnormal two-dimensional echocardiograms, as compared with 0.19±0.019 U per milliliter among patients with normal echocardiograms (P = 0.01). We conclude that heparin administered subcutaneously in a dosage of 12,500 units every 12 hours to patients with acute anterior transmural myocardial infarction is more effective than a lower dosage (5000 units every 12 hours) in preventing left ventricular mural thrombosis. (N Engl J Med 1989; 320:352–7.)
A8.1 NCF1-deficient mice with impaired oxidative bursthave a more aggressive progression of dextran sulfate sodium (DSS) -induced colitis
Authors: Tiago Rodrigues-Sousa, Ana Ricardo Xavier, Joana Marçal Gomes, Ana Alarcão, Lina Carvalho, Margarida Souto-Carneiro
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Introduction</h3> Intestinal Inflammatory Disease (IID) as a primary immunodeficiency depends on mutations in the NADPH oxidase complex, responsible for the production of reactive oxygen species (ROS). One of the most common clinical patterns in IID is chronic colitis. Ncf1-mutation in mice leads to deficiency in ROS, rendering them susceptible to autoimmunity. As in humans, Ncf1-mutation leads to the lack of ROS in B10. Q mice. We used these mutant mice to study how the lack of ROS influences DSS-induced colitis, its transitional recovery and a second colitis induction. <h3>Material and Methods</h3> Colitis was induced in wild type (WT) and Ncf1-mutant (Ncf1) B10. Q mice by administration of 3,0% DSS in the drinking water for one week. Two experiments were made: the first one where the mice were submitted to a 7 days induction and 21 days of resting, the second one included 7 days of induction, followed by 14 days of resting and another 7 days cycle. Mice were sacrificed before the experiment had started and at days 7, 23 and 30. During the experiment we monitored clinical scores of colitis. The colon was removed and folded into a Swiss roll and sections of the colons were stained with HE. Leukocytes subsets from mesenteric lymph-nodes were analysed by flow citometry. <h3>Results/ Conclusions</h3> The clinical scores were more severe in Ncf1 than WT mice also with a poor recovery. The cell population study showed in Ncf1 an aberrant pro-inflammatory immune response comparing to WT and also a more inefficient recovery. This severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-α, IFN-γ and IL-17A) and phosphorylation of LRRK2. Histological analyses revealed that Ncf1 mice had a more severe disease with poor proximal epithelium recovery, signs of dysplasia and with some of them developing colon carcinoma. These results suggest that ROS are crucial for leukocyte recruitment and tissue-repair in DSS-induced colitis.
Treatment of Acute Thyroiditis with Antithyroid Drugs
Authors: William S. Reveno, Herbert Rosenbaum
Journal: New England Journal of Medicine (1951)

WE have treated 3 patients with acute thyroiditis, all women between forty-two and fifty-one years of age, with antithyroid drugs, with prompt resolution of the disturbance in all. Two additional patients, aged fifty-five and forty-eight, who presented suggestive signs of acute thyroiditis and responded to treatment with thiouracil, are not included in this report because the diagnosis was not so clear-cut as in the others. One of them had a Hashimoto-struma lymphomatosa with a flare-up simulating acute thyroiditis. The other presented comparatively few distinctive symptoms of this disease but showed more evidence of an acute hyperthyroidism.Acute thyroiditis is a . . .
Case 9-2007
Authors: Jean-Michel Vallat, Didier P. Cros, E. Tessa Hedley-Whyte
Journal: New England Journal of Medicine (2007)

A 27-year-old woman had the sudden onset of pain in the feet, more in the left foot than in the right, associated with edema of the lower legs and a rash over the feet and toes. Pain and paresthesia persisted and worsened; a neurologic examination revealed normal motor strength and reflexes but decreased sensation to pinprick in the toes. A diagnostic procedure was performed.