tbuckley/cabot-search huggingface dataset:
S38 The Brd4 Inhibitor, Jq1 Decreases Proliferation And Arrests The Cell Cycle Of Pulmonary Vascular Cells: Implications For Pulmonary Arterial Hypertension
Authors: S. Mumby, N. Gambaryan, I. Adcock, S. Wort
Journal: Thorax (2014)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is an incurable disease characterised by raised pulmonary resistance, resulting from vascular remodelling which leads to right heart failure and death. Recently NF-kB mediated inflammatory gene expression and vascular proliferation/remodelling have been shown to be involved in the pathogenesis of PAH. The expression of subsets of NF-kB-induced inflammatory genes is dependent upon the recruitment of the bromodomains and extra-terminal (BET) family of proteins to the transcriptional activation complex. We hypothesise that inhibition of BET proteins which bind acetylated lysine residues on histones and non-histone proteins will attenuate the hyperproliferative and proinflammatory phenotype of vascular cells. <h3>Methods</h3> Primary human pulmonary vascular endothelial cells (P-EC) were serum starved for 24 h prior to treatment with the Brd4 mimic JQ1+ or JQ1- (inactive enantiomer) in complete (5% FCS) media. P-EC cell proliferation was measured by BrdU incorporation and apoptosis was determined using caspase 3/7 activity. Cell cycle progression was determined by FACs analysis. mRNA levels of cell cycle genes and inflammatory cytokines were measured by RT-PCR. MTT assay was used to measure cell viability. <h3>Results</h3> JQ1+ caused a significant (p &lt; 0.001) and concentration-dependent decrease in P-EC proliferation and an increase in caspase 3/7 activity compared to P-EC treated with JQ1- for 24 h. JQ1+ (1 µM) significantly arrested the cell cycle of P-EC at the G1 phase. This was additionally evidenced by a decrease in the cell cycle genes CDK2, 4 and 6 mRNA levels and a significant increase in the mRNA of the cell cycle inhibitor CDKN1A (p21/cip1) at 4 h. Finally, JQ1+ significantly (p &lt; 0.01) inhibited the mRNA levels of the inflammatory cytokines IL-6 and 8 in P-EC compared to JQ1–. <h3>Conclusion</h3> Inhibition of Brd4 with JQ1 decreases remodelling and inflammation in P-EC via a decrease in proliferation, cell cycle arrest and an increase in apoptosis. Further work is required but Brd4 inhibition may provide therapeutic drugs for the treatment of PAH.
P2-14-10: Are There Variations in Invasive Tumour Characteristics between Different Ethnic Groups?
Authors: B Hariri, M Lo, T Gandamihardja, J Lewis, K Hogben
Journal: Cancer Research (2011)

Abstract Introduction: Studies have shown that ethnic minorities with breast cancer are more likely to present at a younger age and with more aggressive tumours. The aim of this study was to examine the variation in tumour characteristics and surgical outcomes in different ethnic groups in our breast unit over a 12-month period. Methods: A retrospective study was performed on all patients with a new diagnosis of breast cancer, either screen-detected or symptomatic, between January to December 2009. Using our Trust databases, data on patient demographics, tumour characteristics, and ethnicity were collected. Where ethnicity was not documented, patients were contacted by telephone to complete the database. Those unable to be contacted were excluded from the study. Other exclusion criteria include those with recurrent ipsilateral breast cancer. Results: A total of 270 patients (265 females) were included in our study, of which 235 (87%) had invasive cancers (ductal carcinoma, lobular carcinoma, tubular carcinoma, mucinous carcinoma, cribriform carcinoma, papillary carcinoma, sarcoma) and the remaining 35 patients (13%) had non-invasive cancers (ductal carcinoma in-situ, lobular carcinoma in-situ, papilloma, columnar cell hyperplasia). We were unable to contact 23 (8.5%) patients to ascertain their ethnicity, and therefore these have been excluded from our results. Table 1. Tumour characteristics and surgical intervention in patients with invasive breast cancer in 2009 Conclusion: We found that the age of breast cancer presentation was lowest in Black and Asian patients (mean age 52 years and 54 years, respectively), compared to White (mean age 59 years). Furthermore, compared to white patients, tumours in Asian patients were larger (62.5% vs 47.2%), of higher grade (83.3% vs 75.2%), more likely to be ER negative (16.7% vs 12.4%), and tended to be lymph node positive (41.7% vs 34.2%). These may explain the higher mastectomy rate in Asian patients (n=12, 50%). The reason for the younger presentation age in the ethnic Asian group is unclear. However, it is possible that their cancer may have different tumour biology. Other studies have suggested reasons such as birth cohort effect and obesity. Reflecting the United Kingdom's population the majority of patients that present to our breast unit are White and the number of Asian patients remains small. An increase in the sample size may strengthen our results. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-10.
Azygos Lobe
Authors: AMELIA JIMÉNEZ-HEFFERNAN, PABLO I. CONTRERAS, ANTONIO ORTEGA, CRESCENCIO CAMACHO, FRANCISCO J. RODRIGUEZ-VERA, JUAN C. SANCHEZ
Journal: Clinical Nuclear Medicine (2001)

JIMÉNEZ-HEFFERNAN, AMELIA M.D.; CONTRERAS, PABLO I. M.D.; ORTEGA, ANTONIO M.D.; CAMACHO, CRESCENCIO M.D.; RODRIGUEZ-VERA, FRANCISCO J. M.D.; SANCHEZ, JUAN C. M.D. Author Information
Hepatoerythropoietic Porphyria: Clinical, Biochemical, and Enzymatic Studies in a Three-Generation Family Lineage
Authors: Arnold C. Toback, Shigeru Sassa, Maureen B. Poh-Fitzpatrick, Jay Schechter, Edith Zaider, Leonard C. Harber, Attallah Kappas
Journal: New England Journal of Medicine (1987)

Hepatoerythropoietic porphyria is caused by a marked deficiency in the activity of uroporphyrinogen decarboxylase, an enzyme that is essential for heme biosynthesis. It has been hypothesized that uroporphyrinogen decarboxylase deficiency is inherited as a homozygous defect in the disease. This suggestion has been supported by reports of a deficiency of the enzyme in parents of patients with the disorder. Further confirmation would be provided by demonstrating a similar uroporphyrinogen decarboxylase deficiency in the offspring of such patients. This study follows the enzymatic defect throughout three generations of a family in which a second-generation male was shown to have hepatoerythropoietic porphyria. Detailed biochemical and enzymatic analyses revealed a moderate deficiency of uroporphyrinogen decarboxylase in both the proband's parents and in his three children, all of whom were asymptomatic. The mildness of the clinical symptoms in the proband correlated with a higher level of residual enzyme activity than that in previously described patients. We conclude that clinically manifested hepatoerythropoietic porphyria results from the homozygous inheritance of a defect in the uroporphyrinogen decarboxylase gene, that the severity of clinical symptoms is probably related to the level of residual enzyme activity, and that the genetic defect of uroporphyrinogen decarboxylase in hepatoerythropoietic porphyria can be heterogeneous.
AB0653 Contribution of salivary gland ultrasonography to the diagnosis of sjÖgren’s syndrome: Towards new diagnostic criteria?
Authors: D. Cornec, S. Jousse-Joulin, A. Saraux, T. Marhadour, B. Cochener, E. Nowak, S. Boisramé-Gastrin, J.-O. Pers, V. Devauchelle-Pensec
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> AECG classification criteria are largely used as diagnostic criteria for primary Sjögren's syndrome (pSS) in the clinical setting, but their diagnostic value has not been studied in cohorts of patients with suspected pSS since their publication in 2002. They do not include salivary gland ultrasonography (SGUS), which is a non-invasive procedure to assess salivary glands involvement during pSS <h3>Objectives</h3> The objective of this work was to determine the accuracy of SGUS for diagnosing pSS and to suggest modifications of AECG classification criteria. <h3>Methods</h3> We conducted this cross-sectional study in a prospective cohort of patients with suspected pSS established between 2006 and 2011. Both parotid and submandibular glands were examined by ultrasonography, and the echostructure of each gland was rated between 0 and 4. We also evaluated the size of the glands, and parotid blood flow by Döppler waveform analysis. The reference standard was a clinical diagnosis of pSS by a group of experts blinded to the results of SGUS. <h3>Results</h3> Of 158 included patients, 78 patients were diagnosed by the experts as having pSS, including 61 (78.2%) who met AECG criteria. All AECG items were significantly associated with a pSS diagnosis except xerostomy and xerophtalmy. Döppler analysis and measurement of gland size did not display good diagnostic properties. By ROC curve analysis of echostructure scores, the best performance was for the maximal score of one of the four glands in each patient. Optimal cut-off was ≥2/4, with 62.8% sensitivity and 95.0% specificity. The diagnostic value of the echostructure score was similar when the patients were stratified according to the disease duration. A weighted score was constructed using the five variables selected by logistic regression analysis: (salivary flow*1.5) + Schirmer*1.5 + (salivary gland biopsy*3) + (SSA/SSB*4.5) + SGUS*2. By ROC curve analysis, a score ≥5/12.5 had 85.7% sensitivity and 94.9% specificity, compared to 77.9% and 98.7% for AECG criteria (figure). Internal validation through bootstrapping analysis showed good performance of this score. <h3>Conclusions</h3> SGUS has good diagnostic properties for pSS. Modifications of AECG criteria including the addition of an SGUS score notably improve their performance. <h3>Disclosure of Interest</h3> None Declared
Abstract 1630: Vitamin E delta-tocotrienol prevents azoxymethane-induced colon carcinogenesis progression in Fisher-344 rats
Authors: Jose M. Pimiento
Journal: Cancer Research (2012)

Abstract Background: Chemoprevention by bioactive food components has emerged as an alternative approach for the prevention of colorectal carcinogenesis. We have shown that natural vitamin E delta-tocotrienol is the most bioactive tocotrienol against pancreatic cancer. This study evaluated the efficacy of vitamin E delta-tocotrienol feeding in the prevention of azoxymethane-induced colorectal polyps and cancer formation in Fisher-344 rats. We also evaluated the antitumor activity of vitamin E delta-tocotrienol in colorectal cancer cell lines and in APCmin mouse model. Methods: The in vivo antitumor activity of delta-tocotrienol was evaluated in azoxymethane-treated Fisher-344 rats. Rats were administered azoxymethane (15 mg/kg, SC, 2 x in 2 weeks) then randomly selected into 3 groups: 1) No treatment, 2) Vehicle (ethanol extracted olive oil, 1 ml/kg, PO twice daily and 3) Delta-tocotrienol (200 mg/kg, PO) twice daily for 20 or 40 weeks. The animals were euthanized and the colons were examined for polyps and cancers. Colon tissues were fixed in buffered formalin, embedded, cut and stained with H &amp; E and scored. The APCmin mice were treated with 1) vehicle (olive oil, 1 ml/kg, PO) twice daily for 2 weeks and 2) Delta-tocotrienol (200 mg/kg, PO) twice daily for 2 weeks. Mice euthanized and colon tissues isolated and evaluated for proliferation and apoptosis by immunohistochemistry staining. The in vitro anti-tumor activity of delta-tocotrienol was preformed in human colorectal cancer cell lines HCT-116, HT-29 and SW 480. Results: Delta-tocotrienol feeding to azoxymethane-treated rats significantly reduced (75%, p&amp;lt;0.002) the number of polyps formation compared to untreated or vehicle treated rats. Moreover, the number of colon cancer formation was reduced (70%, p&amp;lt;0.001) with delta-tocotrienol feeding compared to untreated or vehicle treated rats. In colonic tissues of APCmin mice, delta-tocotrienol feeding decreased proliferation (Ki-67), induction of p27, and induction of apoptosis (caspase-3) compared to vehicle treated mice. Delta-tocotrienol also inhibited cell proliferation and induced apoptosis in HCT-116, HT-29 and SW 480 cell lines, through induction of nuclear factor kappa-B (NF-kB) and degradation of beta-catenin. Conclusion: These data show the efficacy of natural vitamin E delta-tocotrienol against the early stages of colorectal carcinogenesis as well as anti-proliferative and apoptotic activity in colorectal cancer both in vitro and in vivo. Delta tocotrienol likely targets NF-kB and beta-catenin signaling pathways, suggesting its potential clinical usefulness for the prevention of human colorectal cancer. 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 1630. doi:1538-7445.AM2012-1630
AB1005 Non-monetary health care resources utilization in knee and hip osteoarthritis and associated factors. A national study
Authors: R. Lopez-Gonzalez, J.M. Lopez-Gomez, L. Carmona, E. Loza, E. Batlle
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To analyze knee and hip osteoarthritis (OA) healthcare resources utilization and associated factors in Spain. <h3>Methods</h3> Consecutive patients aged 50 or older with symptomatic and radiological knee and/or hip OA, who were attended in primary care centers in all regions of Spain were included. Information on demographics, health status (Short Form 12 Health Survey), comorbidities (Charlson Index), clinical (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) and radiologic OA severity (Kellgren/Lawrence [K/L] scale), data related to OA health resources utilization: number of medical and nonmedical visits related to OA, diagnostic and imaging tests, and treatments: analgesic, nonsteroidal antiinflammatory drugs (NSAID) in the previous 6 months were collected in 2 separate, structured, and detailed interviews. Descriptive analyses were performed, and the predictors of OA health resources utilization were assessed in multivariate linear regression models. <h3>Results</h3> A total of 1,071 subjects were analyzed (74% women with a mean age of 71 years ± 9 years, mostly retired or housewives). Patient's knee OA mean duration was 7 years ± 8 years, 3 years ± 6 years for hip OA. The mean (standard deviation) of the healthcare resources use was: 13.1 (17.3) for visits related to OA, 8.95 (7.98) visits to primary care physicians, 0.18 (0.70) visits to rheumatologists, 0.71 (0.88) blood analyses, 1.47 (1.47) knee X-rays, 1 (1.09) hip X-rays, 0.11 (0.54) local steroid injections. We found 114 of urgent visits to the hospital, of which 53 required a hospitalization, with a mean length of stay of 0.43 days (3.44), and almost 100% of patients had tried analgesics and NSAIDs. Worse health status was associated with primary care visits, women and comorbidities with OA hospitalizations, women and OA severity with X-rays, WOMAC score with blood analyses, comorbidities and WOMAC score with the use of analgesic, and the WOMAC score with the use of NSAID. There were no predictors of rheumatology visits. <h3>Conclusions</h3> The healthcare resources utilization of knee and hip OA is substantial; most of it is based on clinical visits. Disease severity, poor health status and comorbidities were associated with healthcare use. Surprisingly, there were no predictors of rheumatology visits, though were expected. Therefore, in order to improve healthcare visits, clinical pathways and protocols between primary care and rheumatologist might be developed. <h3>Disclosure of Interest</h3> None Declared.
T-cell immunity to Kaposi sarcoma–associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells
Authors: Shereen Sabbah, Ya Jankey Jagne, Jianmin Zuo, Thushan de Silva, Mohammad M. Ahasan, Christian Brander, Sarah Rowland-Jones, Katie L. Flanagan, Andrew D. Hislop
Journal: Blood (2012)
Evidence for Genetic Associations between Asthma, Atopy, and Bronchial Hyperresponsiveness
Authors: JANE R. CLARKE, MARK A. JENKINS, JOHN L. HOPPER, JOHN B. CARLIN, CAROL MAYNE, DAVID G. CLAYTON, MARITA F. DALTON, DIANE P. HOLST, COLIN F. ROBERTSON
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We measured asthma in the last 12 mo, diagnosed by a respiratory physician at interview; atopy, defined by a positive skin prick test to any of eight common allergens; and bronchial hyperresponsiveness (BHR) to hypertonic saline, in 381 twin pairs aged 8 to 18 yr selected from the Australian Twin Registry—183 monozygous (MZ) and 198 dizygous (DZ). The associations between twins, as measured by an odds ratio, were greater in MZ pairs compared with DZ pairs for asthma: 25.6 (95% confidence interval 11.3– 57.8) versus 1.9 (1.0–3.5); atopy: 14.6 (7.1–30.1) versus 2.5 (1.4– 4.5); and BHR: 14.1 (6.4–31.0) versus 4.2 (2.1–8.6) (all p < 0.002). The associations between each pair of traits within an individual were slightly greater than the association between one trait in a twin and the other trait in the cotwin (cross-trait cross-pair) in MZ pairs. Further, the associations in MZ pairs were greater than in DZ pairs (p < 0.05). Under the assumptions of the classic twin model, these data suggest that the strong cross-sectional associations between these three traits are due to an overlap between the genetic factors involved in each of these three traits.
Bortezomib Enhances the Efficacy of Fulvestrant by Promoting the Aggregation of the Estrogen Receptor in the Cytoplasm.
Authors: D. Germain, U. Bahadur, M. Halpern, K. Adelson, G. Raptis, S. Waxman, Y. Ishii
Journal: Cancer Research (2009)

Abstract Background: Aromatase inhibitors (AIs) are standard treatment for Estrogen Receptor (ER)+ breast cancers in post-menopausal women where the main source of estradiol comes from adipose tissue when the aromatase enzyme converts androgens to estrogens. However, in premenopausal women, functioning ovaries flood the body with estrogens, and aromatase inhibitors used alone offer no therapeutic benefit. In addition to tamoxifen and aromatase inhibitors, estrogen receptor down-regulators, are a third type of anti-estrogen. The first of this class to be FDA approved is Fulvestrant, which acts by promoting the proteosomal degradation of the ER. Like tamoxifen, fulvestrant binds directly to the ER but while tamoxifen has both antagonist and agonist effects on the ER, fulvestrant is a pure antagonist. Other important advantages of fulvestrant over tamoxifen are that 1) fulvestrant prevents the ER from binding DNA, 2) fulvestrant is not linked to increased risk of endometrial cancer, 3) fulvestrant promotes permanent degradation of the ER.The molecular machinery leading to the degradation of the ER in the nucleus following fulvestrant treatment is well described and correlates with its ubiquitination in the nucleus. A less well-recognized mechanism, is fulvestrant’s ability to promote the aggregation of the newly synthesized ER in the cytoplasm. Understanding that protein aggregates are toxic when not eliminated by the proteasome, we took advantage of this effect of fulvestrant to ask whether combining fulvestrant with the proteasome inhibitor Bortezomib could enhance the efficacy of Fulvestrant.Results: We found that bortezomib enhances the aggregation of the ER in the cytoplasm following treatment with fulvestrant. Further, these aggregates were found to be insoluble and to activate the unfolded protein response (UPR), a stress response that leads to cell death. Further, bortezomib is able to prevent the activation of cytoprotective responses linked to the acquisition of fulvestrant resistance. Furthermore, in a breast cancer mouse model of tamoxifen resistance, the combination induced tumor regression.Conclusion: We conclude that adding bortezomib to fulvestrant enhances its efficacy by taking advantage of a previously poorly recognized mechanism–fulvestrant’s induction of ER aggregation in the cytoplasm. Further, our data suggest that this strategy will block the ability of cells to acquired resistance to fulvestrant. Our group has developed a clinical trial that will test this combination. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5142.
THU0285 Long-Term Safety and Efficacy of Tacrolimus for Lupus Nephritis Patients –Interim Analysis of Post Marketing Surveillance in 1375 Patients in Japan (Trust Study)
Authors: T. Takeuchi, N. Wakasugi, H. Makino
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Tacrolimus (TAC) is an immunosuppressive macrolide that blocks T cell activation by specifically inhibiting calcineurin, and it is widely administered following organ transplantation. Recently some randomized studies have shown that TAC is an effective maintenance treatment for lupus nephritis (LN)(1-2), and TAC has been approved in Japan and some Asian countries for LN. However, the safety and efficacy including the long-term outcome of TAC for LN patients in the real clinical setting may not be clear enough. <h3>Objectives</h3> To assess the safety and efficacy including long-term outcome of TAC for LN patients in the real clinical setting, post-marketing surveillance was conducted. <h3>Methods</h3> Patients were registered centrally in an all-patient investigation system between 2007 and 2010 from 296 medical sites. The registered patients will be followed for 10 years, and the safety and efficacy were evaluated at weeks 4, 8, 12 and 28,1 year and every year thereafter. <h3>Results</h3> This interim analysis included all the registered 1375 patients, and the median follow-up period was 28.7 months (Range:0.1 - 62.6 months). The most common serious adverse drug events were infections, in which herpes zoster, bacterial pneumonia and cellulitis were observed most frequently, at the incident rates of 0.7%, 0.6% and 0.5%, respectively. The spot urine protein : creatinine ratio (P/C ratio) was significantly decreased from four weeks after the TAC treatment (Mean value : 1.7 at baseline to 1.1 at four weeks, p&lt;0.001 and 0.7 at two years, p&lt;0.001). Also, the serum complement C3 and anti-ds DNA antibodies were significantly improved from four weeks after treatment (Mean value, complement C3 : 68mg/dL at baseline to 73mg/dL at four weeks, p&lt;0.001 and 81mg/dL at two years, p&lt;0.001, anti-ds DNA antibodies : 42IU/mL at baseline to 29IU/mL at four weeks, p&lt;0.001 and 20IU/mL at two years, p&lt;0.001). <h3>Image/graph</h3> <h3>Conclusions</h3> TAC is well tolerated and effective in Japanese patients with LN in the real clinical setting. <h3>References</h3> N.Miyasaka, S. Kawai, H.Hashimoto. Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. <i>Mod Rheumatol.</i> 2009;19:606-615 W Chen, Q Liu, W Chen, <i>et al</i>. Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. <i>Lupus</i> 2012;21(9):944-952 <h3>Acknowledgements</h3> The authors wish to thank all investigators for their contributions to the implementation of this study. <h3>Disclosure of Interest</h3> T. Takeuchi Grant/research support from: Astellas Pharma Inc., N. Wakasugi Employee of: Astellas Pharma Inc., H. Makino Grant/research support from: Astellas Pharma Inc.
Local Health Services in Massachusetts
Authors: Robert E. Archibald, Autino Fiore, Solomon L. Skvirsky
Journal: New England Journal of Medicine (1948)

MASSACHUSETTS has long been recognized as a leader in many phases of public health. However, there has been a considerable lag in the provision of adequate local health facilities, owing in part to the heritage of local autonomy. Our interpretation of adequate facilities is the complete coverage of the state by local health units, conducted by the official governing body of the units and financed wholly or in part with local funds. These units should be staffed with full-time, well trained personnel rendering at least basic health services to all people of the Commonwealth. Until such local health units become . . .