tbuckley/cabot-search huggingface dataset:
Abstract 5399: S100A9 drives MDSC migration and contributes to tumor progression by inhibiting the immune response
Authors: Thomas Condamine, Pingyan Cheng, Je-In Youn, Myrna L. Ortiz, Thomas Vogl, Johannes Roth, Dmitry I. Gabrilovich
Journal: Cancer Research (2012)

Abstract S100A9 is a pro-inflammatory molecule, secreted by myeloid cells, which has been reported to recruit leukocytes to the sites of inflammation or tumors. We have previously found that up-regulation of S100A9 expression in myeloid progenitor cells in cancer resulted in inhibition of DC differentiation and promotion of expansion of myeloid-derived suppressor cells (MDSC). It remained unclear how S100A9 could regulate MDSC expansion and function. In this study we evaluated the effects of secreted (extracellular) vs intracellular S100A9 on MDSC. Recombinant S100A9 or S100A8 proteins separately or as heterodimers did not promote MDSC expansion from hematopoietic progenitor cells (HPC), or affect their suppressive activity. However, recombinant proteins had a strong chemotactic effect on MDSC. Interestingly, this effect on immature myeloid cells isolated from naïve tumor-free mice was substantially lower. To study intracellular activity of S100A9 we used S100A9 transgenic (Tg) and knockout (KO) mice. Mice were injected with several different weakly and strongly immunogeneic tumors. As expected Tg mice had increased expansion of MDSC and KO mice had substantially reduced number of these cells. Different levels of MDSC did not affect the growth of weakly immunogeneic tumors. In contrast, overexpression of S100A9 in mice lead to significantly accelerated growth of immunogenic tumors. Lack of S100A9 resulted in fast rejection of immunogeneic tumors. Our data indicate that extracellular and intracellular S100A9 had different signalling in myeloid cells and apparently affect different aspects of their function. S100A9 over-expression, in vivo, inhibits the immune response, most likely by promoting MDSC accumulation and/or suppressive activity. Our data suggest that targeting of S100A9 in cancer can be an attractive therapeutic option. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5399. doi:1538-7445.AM2012-5399
DOES PRE-PREDILATATION PRIOR TO DELIVERY OF EMBOLIC PROTECTION IMPACT IN-HOSPITAL CVA/TIA IN PATIENTS UNDERGOING CAROTID STENTING?
Authors: Ali Aboufares, James Wilentz, Daniel Soffer, Ming Liao, Christina Brennan, Monica Losquadro, Ajay Kirtane, William Gray, Sriram Iyer, Gary Roubin
Journal: Journal of the American College of Cardiology (2015)
ISSUES OF CONVENTIONAL META-ANALYSIS FOR TIME-TO-EVENT OUTCOMES: REANALYSIS RESULTS OF THE EFFICACY AND SAFETY OF NOVEL ORAL ANTICOAGULANTS VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION USING RECONSTRUCTED INDIVIDUAL-LEVEL DATA
Authors: Masayuki Kaneko, Hajime Uno
Journal: Journal of the American College of Cardiology (2016)
Health Profile: Challenging doctors: an interview with England's chief medical officer
Authors: R Smith
Journal: BMJ (1994)

Professor Ken Calman, the chief medical officer in England, is said by many “to have a brain the size of a planet.” Before taking up his present post - in 1991 - he was professor of clinical oncology in Glasgow, dean of postgraduate medicine in the west of Scotland, and chief medical officer in Scotland.

RS: Many people think that the CMO doesn't have anything like the influence that he had back in the days of, for example, Sir George Godber, who was chief medical officer from 1960 to 1973. Is this true?

KC: You must look at this historically. Each CMO has found a particular niche at a particular time. George Godber was CMO in the 1960s, a time of expansion. John Simon was CMO in the 1850s and concentrated on public health issues. George Newman in the 1920s tackled - remarkably - general education, physical education, and medical education. Wilson Jamieson in the 1940s concentrated on the new NHS and setting up the World Health Organisation.

I am faced with a particular range of issues in a climate that has changed considerably since the 1960s, and my job is to look at the opportunities and see what I can do with them - to improve the health of the people and ensure that doctors are enabled to perform to the highest possible standards.

RS: So on particular subjects you might have as much influence as they had?

KC: Of course. Let me just give you three examples. The CMO - and by the CMO I mean myself and my team - remains very much the leader in shaping medical education; the Health of the Nation; and outcomes, effectiveness, and audit. And what could be more important than these?

RS: What is the relationship between the CMO and the …
Absence of Hexosaminidase a and B in a Normal Adult
Authors: Jean-Claude Dreyfus, Livia Poenaru, Lars Svennerholm
Journal: New England Journal of Medicine (1975)

In the course of screening for heterozygotes for beta-hexosaminidase deficiency, the serum and white cells of a clinically normal father of deficient children were found to have an apparent deficiency for both hexosaminidases A and B, assayed with an artificial substrate, 4-methylumbelliferyl-beta-glucosaminide. No inhibitor was present. Assayed with a natural substrate, n-acetylgalactosaminyl beta 1-4 galactosyl beta 1-4 glucosyl ceramide, which had been isolated from the brain of a patient with Tay--Sachs disease and labeled in the terminal n-acetyl-galactosamine, a value in the heterozygote range was found. It was concluded that the proband is probably a double heterozygote for two mutations; one is the classic Sandhoff type (lack of hexosaminidases A and B), giving rise to deficient offspring when combined with the same mutation borne by the wife. The other obscures any activity with the artificial substrate but allows an action on natural substrates, explaining the normal life of its carrier.
Abstract 3333: Cancer stem cell-mediated regulation of Myc overexpressing medulloblastoma cells on proliferation, migration and invasion
Authors: Jun Bum Park, Dong Ok Kim, Yoon Hwan Ra, Young Shin Ra
Journal: Cancer Research (2012)

Abstract Medulloblastoma (MB) is the most common and malignant pediatric brain tumor. Myc amplification was frequently shown in the tumor. Hereby cancer stem cells are being issued lately was investigated whether it is associated with Myc and its contributions. MB cell lines - UW228, UW228-Myc, UW426 and UW426-Myc were used for following assays. Myc overexpressing cells of two kinds of cells were shown significantly higher proliferation rate than counterpart cells by cell proliferation assay. In particular, the extent of difference in UW228-Myc was bigger than in UW426-Myc. Using cell cycle analysis, DNA contents in both UW228-Myc and UW426-Myc were mainly accumulated in G2/M phase compared with their each control, suggesting that cells overexpressing Myc have faster proliferation rate. In addition, two UW228-Myc and UW426-Myc cells were demonstrated more increased self-renewal capacities by colony-forming assay versus UW228 and UW426, respectively. For migration and invasiveness, both Myc overexpressing cells increased in comparison with each control by wound-healing assay and invasion assay using Matrigel chamber. Interestingly UW228-Myc cells were shown nearly six times higher invasiveness than in UW228 cells. In contrast, the disparity of that in UW426 and UW426-Myc cells was just about two times. It is verified that why Myc overexpressing cells have more dominant proliferation, self-renewal, migration and invasion abilities than corresponding controls by western blot assay. The results showed strongly increased expression of migration, invasion-related markers (p-AKT, p-ERK1/2 and Rac1) and cancer stem cell-related markers (Nestin, CD133, Oct3/4 and SOX2), especially in UW228-Myc cells. In conclusion, Myc expression induces not only cell proliferative and self-renew propensities, but also migration and invasiveness by mediating cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3333. doi:1538-7445.AM2012-3333
FRI0557 Estimation for the remision cutoff point for hospital universitario de la princesa index (HUPI) in a longitudinal cohort of arthritis of recent onset. validation in a long-term arthritis register.
Authors: L. Sala, I. Castrejón, L. Carmona, A. Ortiz, E. Toledano, S. Castañeda, A. García Vadillo, I. González Álvaro
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Our group has recently described a new index to assess disease activity in patients with early arthritis (EA). The Hospital de Universitario de la Princesa Index (HUPI) is easy to calculate and avoids some biases existing in currently validated indexes. The HUPI is the simple sum of the scores assigned to each of the variables included in the DAS (count of swollen and painful joints, global assessment of the patient's disease and acute phase reactants) according to their interquartile distribution in our EA population (0 to 3 according to the quartile). The index allows the use of ESR and / or CRP as available. We have previously shown that HUPI is as accurate as DAS28 or SDAI, with the advantage to have greater sensitivity to change<sup>1</sup> <h3>Objectives</h3> To estimate the cutoff point for remission in HUPI and validate it in a long term RA cohort <h3>Methods</h3> We used clinical data from 568 visits in 207 patients from our EA register. Three definitions of remission were used: Boolean and SDAI 2011 ACR/EULAR criteria, as well as that established by six experienced rheumatologists by consensus. In addition, the six rheumatologist established the low, moderate and high disease activity levels in the EA cohort. We also used EMECAR (a national cohort of rheumatoid arthritis consisting in 2000 visits in 789 patients randomly selected from 34 centers in Spain) in which remission was define by Pinals et al preliminary criteria. The cutoff points were selected considering the best combination of sensitivity and specificity for each of them using ROC analysis. <h3>Results</h3> The best cutoff point for remission in the EA population was 2.5 with the two ACR/EULAR criteria SDAI &lt;3'3 (Specificity 90%, Sensitivity 94%) or Boolean (Sp 84%, Se 95%), as well as for the expert opinion (S e89%, Sp 89%). It was also valid for the long term RA EMECAR cohort (using Pinals criteria: E 49%, S 95%). The remaining cutoff points were 5 to discriminate between mild and moderate activity (S 67%, E 92%) and 9 to discriminate between moderate and high (S 93%, E 89%). The area under the curve was higher in value cutoffs for remission and high activity than for the point which discriminates between low and intermediate. <h3>Conclusions</h3> The cutoff point for remission in HUPI show high sensitivity and specificity in different populations. <h3>References</h3> - Castrejon I et al. Development and validation of a new disease activity index as a numerical sum of 4 variables in patients with early arthritis. Arthritis Care Res (Hoboken). 2012. PMID: 23002022 <h3>Acknowledgements</h3> This study was supported with funding from FIS ISCIII PI11/00551, PI11/00505 and RETICS RD08/0075 (RIER). <h3>Disclosure of Interest</h3> None Declared
Serum nortriptyline levels in nursing mothers and their infants
Authors: K L Wisner, J M Perel
Journal: American Journal of Psychiatry (1991)

The nortriptyline levels of seven depressed mothers and their breast-fed infants were obtained. Nortriptyline was not detected in the infants' sera. However, two of four infants evaluated developed low concentrations of 10-hydroxynortriptyline. No adverse effects were observed.
Acute Renal Failure in McArdle's Disease
Authors: Jean-Pierre Grünfeld, Dominique Ganeval, Jacques Chanard, Michel Fardeau, Jean-Claude Dreyfus
Journal: New England Journal of Medicine (1972)

Two patients with McArdle's disease had acute renal failure associated with acute rhabdomyolysis. Both patients had only mild muscular symptoms before the onset of acute rhabdomyolysis. In one case the course of acute renal failure was marked by transient hypercalcemia at the onset of the diuretic phase. In one patient no phosphorylase activity was observed, and no immunologically reactive phosphorylase was found in muscle-biopsy specimens. In the other a small amount of muscle phosphorylase (5 and 10 per cent of normal, depending on the method used) was detected by histochemical, biochemical and immunologic methods. The phosphorylase activity detected in this second patient did not remain stable, suggesting that such activity may be due to an abnormal, unstable molecule. The data suggest that more than one molecular mechanism may be involved in muscle phosphorylase deficiency.
Role of transrectal ultrasound in the recurrence of rectal cancer
Authors: A Isern, C Fernández, K Hernandez, M Bronstein, J Salazar, S Fernandez
Journal: Endoscopy (2011)

Transrectal ultrasonography (TRUS) has an important role in the evaluation of rectal tumors. It is used to determine the depth of tumor spread into the rectal wall, the extent of tissue invasion to neighboring organs, and also to explore the peri-rectal environment and detect possible metastatic nodes. TRUS has proven to be a very accurate imaging technique in the preoperative staging of rectal tumors, contributing to improve therapeutic management and prognosis. Recurrence rates after surgery are approximately 3 to 35% (depending on the preoperative staging), decreasing after radiation to 10%. The recurrence risk is greatest in the first 18 to 24 months after surgery. TRUS guided biopsy at the anastomotic or perianastomotic tissue allows differentiation between malignant and benign lesions. We suggest that TRUS can therefore be used to detect early local recurrence and/or benign post operative complications at the site of anastomosis.
Abstract 3830: Type 2 cGMP-dependent protein kinase regulates proliferation in the colon
Authors: Rui Wang, In-Kiu Kwon, Darren D. Browning
Journal: Cancer Research (2011)

Abstract Signaling through cGMP has previously been found to play a role in tissue homeostasis in the intestinal mucosa but the mechanism is not known. Type 2 cGMP-dependent protein kinase (PKG2) is a major cGMP effector in the intestinal epithelium but its role in tissue homeostasis has not previously been examined. The present studies have tested the importance of PKG2 in the regulation of proliferation and differentiation in the mouse colon and in colon cancer cell lines. RT-PCR analysis confirmed that PKG2 is expressed in normal colon mucosa, and although there was no difference in colon tumors, it was undetectable in established colon cancer cell lines. Ectopic expression of PKG2 in LS174T and HT29 cells decreased colony formation in clonogenic assays. This effect of PKG2 on colon cancer cells was not due reduced cell viability but was associated with an increase in G1 arrested cells and increased expression of the differentiation markers CDX2 and MUC2. Consistent with an anti-proliferative and pro-differentiation role of PKG2 in the colon, we observed increased proliferation and larger crypt size in PKG2-/- mice compared to wild type siblings. In addition, there were significantly less mature goblet cells in PKG2-/- mice relative to controls when measured by histological staining with Alcian blue or by immunostaining with anti-MUC2 antibodies. Recent reports suggest that PKG2 might affect differentiation by regulating the transcriptional repressor Sox9. We found that PKG2 could phosphorylate Sox9 at Ser181 in both colon cancer cell lines and in the mouse colon at a position 2/3rd into the crypt. In the colon cancer cell lines, phosphorylation of Sox9 by PKG2 did not affect expression or nuclear localization, and was not sufficient for the regulation of MUC2 or CDX2 expression. The work presented here demonstrates a novel anti-proliferative and pro-differentiation role for PKG2 in the colon, which has an important function in tissue homeostasis. The ability of PKG2 to reduce growth and increase expression of MUC2 and CDX2 tumor suppressors suggests that PKG2 may have therapeutic significance in colon cancer. 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 3830. doi:10.1158/1538-7445.AM2011-3830
Colchicine Myopathy and Neuropathy
Authors: Ralph W. Kuncl, Greg Duncan, Danny Watson, Kathy Alderson, Michael A. Rogawski, Marilyn Peper
Journal: New England Journal of Medicine (1987)

Although colchicine has been used for centuries, its neuromuscular toxicity in humans is largely unrecognized. In this report we describe a characteristic syndrome of myopathy and neuropathy and present 12 new cases of the condition. Colchicine myopathy may occur in patients with gout who take customary doses of the drug but who have elevated plasma drug levels because of altered renal function. It usually presents with proximal weakness and always presents with elevation of serum creatine kinase; both features remit within three to four weeks after the drug is discontinued. The accompanying axonal polyneuropathy is mild and resolves slowly. Electromyography of proximal muscles shows a myopathy that is marked by abnormal spontaneous activity. Because of these features, colchicine myoneuropathy is usually misdiagnosed initially, either as probable polymyositis or as uremic neuropathy. The myopathy is vacuolar, marked by accumulation of lysosomes and autophagic vacuoles unrelated to necrosis or to the mild denervation in distal muscles. The morphologic changes in muscle suggest that the pathogenesis involves disruption of a microtubule-dependent cytoskeletal network that interacts with lysosomes. Correct diagnosis may save patients with this disorder from inappropriate therapy. (N Engl J Med 1987; 316: 1562–8.)
P2-15-12: Management Strategy of Early-Stage Breast Cancer Patients: With or without Axillary Lymph Node Dissection.
Authors: D Yamamoto, K Tanaka, Y Tsubota, H Yosida, S Kanemastu
Journal: Cancer Research (2011)

Abstract Background: The sentinel lymph node (SLN) biopsy has steadily replaced axillary lymph node dissection (ALND) for staging clinically node-negative breast cancer. However ALND remains the standard management of the axilla when a tumor-positive sentinel lymph node (SLN) is identified. The aim of this study was to evaluate the ALND in local, distant recurrence, and overall survival (OS) in breast cancer patients. Methods: We identified 350 patients with breast cancer (clinically T1/T2N0M0) from the prospective database from five institutions from July 1999 and April 2004. All patient age ranged from 26 to 81 (median 49) years. All patients underwent mastectomy or breast conserving surgery (BCT) combined with either ALND or no ALND. Criteria of negative ALN metastasis are that minor axis of ALN is under 5 mm on CT images and fat tissue in the hilum of ALN does not disappear on ultra-sound images. In the case that hormone receptor expression is positive, pt was administered for 5 years. In the case of T1c or T2 under 70 years old, neoadjuvant and/or adjuvant anthracycline-based chemotherapies were administered. After surgery, patients without ALND/with ALND received tangential irradiation at the region of breast. ALND and no ALND groups were compared for incidence of local, regional, distant recurrence, and overall survival. Results: Patients with ALND (n=350) were compared with no ALND group (n=126). There were significant differences in primary tumor size, histology, nuclear grade, presence of LVI, ER/PgR/HER2 status between the two groups. Five years OS was 97.9% in ALND group, it was 98.0% in no ALND group (p&amp;gt;0.01). Further there was no significant difference between two groups in local, regional, and distant recurrence. Conclusions: These results indicate that ALND is omissible for cT1/T2N0M0 breast cancer by a combination of hormone therapy, neoadjuvant/adjuvant chemotherapy, and irradiation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-12.
S36 P38 MAPK: An Important Pathway in the Pathobiology of Pulmonary Hypertension and Pulmonary Vascular Remodelling
Authors: AC Church, R Wadsworth, G Bryson, DJ Welsh, AJ Peacock
Journal: Thorax (2012)

The p38 MAPK pathway is increasingly recognised as important in inflammation leading to systemic vascular disease but its role in pulmonary vascular disease is unclear. Our group has previously identified the p38MAPKα isoform to be critical in hypoxic-induced proliferation of pulmonary artery fibroblasts, a key step in the pathogenesis of pulmonary vascular remodelling. This study sought to investigate the role of p38MAPK in animal models of pulmonary hypertension and in human disease. <h3>Methods</h3> Sprague Dawley rats were exposed to chronic hypoxia for 14 days and received a selective p38 MAPKα inhibitor from day 1 in a prevention strategy, or after 14 days in a treatment strategy. Both prevention and treatment methods were further employed in a second monocrotaline animal model. Haemodynamic measurements (right ventricular systolic pressure RVSP, right ventricular hypertrophy RVH) were performed, and lungs were removed for immunohistochemistry (IHC) and biochemical analysis. Multiplex ELISA was used to analyse cytokine profile in rat serum. Primary PAF were isolated and siRNA techniques employed to knockdown p38MAPKα. IHC for p38 MAPKα was performed on human tissue from patients with idiopathic pulmonary arterial hypertension. <h3>Results</h3> siRNA to p38MAPKα inhibited the hypoxic induced proliferation of PAFs. Increased levels of total p38 MAPK activity and increased expression of the alpha isoform was found in the lungs of both chronic hypoxic and MCT animals compared to normal. Using the p38 MAPK inhibitor in the chronic hypoxic and monocrotaline <i>in vivo</i> prevention study resulted in lower RVSP and RVH in the drug treated animals (p&lt;0.005). In the reversal study of both animal models the inhibitor reversed established pulmonary hypertension as determined by RVSP and RVH (p&lt;0.001). Both serum and whole lung levels of IL-6 were lower in the drug treated animals compared to normal. Increased expression of p38 MAPK was observed in lungs from IPAH patients compared to control. <h3>Conclusions</h3> Our study suggests p38 MAPK alpha is important in pulmonary hypertension. Inhibition of this pathway can prevent the development of PH and perhaps more clinically relevant, can reverse established disease <i>in vivo</i>. Reduction in IL-6 may be a mechanism underlying this process.