tbuckley/cabot-search huggingface dataset:
Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets
Authors: Zhihong Zhu, Futao Zhang, Han Hu, Andrew Bakshi, Matthew R Robinson, Joseph E Powell, Grant W Montgomery, Michael E Goddard, Naomi R Wray, Peter M Visscher, Jian Yang
Journal: Nature Genetics (2016)

Jian Yang and colleagues propose a method that integrates summary data from GWAS and eQTL studies to identify genes whose expression levels are associated with complex traits because of pleiotropy. They apply the method to five human complex traits and prioritize 126 genes for future functional studies. Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation.
Endoscopic ultrasound-guided retrograde pancreatic stent placement for the treatment of stenotic jejunopancreatic anastomosis after a Whipple procedure
Authors: Hiroyuki Matsubayashi, Yoshihiro Kishida, Kunihiro Shinjo, Kenichiro Imai, Kinichi Hotta, Masaki Tanaka, Naomi Kakushima, Kohei Takizawa, Takashi Mizuno, Yukiyasu Okamura, Hiroyuki Ono
Journal: Endoscopy (2013)

Endoscopic ultrasound (EUS)-guided [1] [2] or percutaneous [3] rendezvous methods have been used for the treatment of stenosis at the jejunopancreatic anastomosis following pancreatoduodenectomy. However, the use of EUS-guided retrograde pancreatic duct stenting has not been reported, even though it may be preferable from the point of view of complications.
THU0538 Association of Interleukin-27 Elevation with Abnormal B Cell Functions in Patients with Sjogren's Syndrome
Authors: L. Zhang, C. Zhao, R. Liu, X. Li, X. Feng, L. Sun
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Interleukin (IL)-27 is a new member of IL-6/IL-12 family involved in isotype switching and plasma cell differentiation of naïve B cells. <h3>Objectives</h3> The objective of this study is to investigate the association of IL-27 with B cell functions in patients with Sjogren9s syndrome (SS), an autoimmune disease characterized by B-cell hyperactivity. <h3>Methods</h3> B cell activation was measured by the percentages of CD40 and CD69 positive cells in total CD19<sup>+</sup> B cells under flow cytometry. Carboxyfluorescein diacetate succinimidyl ester (CFSE) and Annexin V were marked to detect B cell proliferation and apoptosis respectively. CD27 and CD138 were used to identify the trend of CD19<sup>+</sup> B cell differentiation. To verify the role of IL-27 on B cell regulation, peripheral blood mononuclear cells (PBMCs) collected from SS patients and healthy controls were stimulated by B cell activators including anti-CD40, recombinant human IL-4, CpG-ODN and F(ab)2 goat anti-human IgM with or without the presence of IL-27 at the concentration of 50ng/ml. 72 or 96 hours later, cells were harvested and detected for B cell activation, proliferation, apoptosis and differentiation. Levels of several cytokines that have been reported to participate in B cell regulation, including IL-27, IFN-γ, IL-10, IL-4 and BAFF, were detected by ELISA. <h3>Results</h3> Compared with healthy controls, the percentages of active B cells (CD40 or CD69 positive in total CD19<sup>+</sup> B cells) were elevated in SS patients (<i>p both</i> &lt;0.05). B cells from SS patients displayed higher proliferation and apoptosis rate (<i>p both</i> &lt;0.05), and an increased cell differentiation into plasma cells was observed (<i>p</i>&lt;0.05). Serum levels of IL-27 were elevated in SS patients, especially in those with high titers of ANA (197.2±24.48 pg/ml vs. 179.8±9.37 pg/ml, <i>p</i>&lt;0.01) or positive anti-SSA/SSB antibodies. In vitro cultures showed that IL-27 stimulation could increase the percentages of CD40/CD69 and CD138 cells, promote B cell proliferation and IgG secretion. Meanwhile, IL-27 could upregulate several B cell related factors in vitro (484.2±235.9 pg/ml vs. 4718±259.9 pg/ml for IFN-γ, 119.2±39.7 pg/ml vs. 98.58±29.17 for IL-4 and 1711±556.6 pg/ml vs. 1436±660.3 pg/ml for IL-10, p all &lt;0.05). <h3>Conclusions</h3> IL-27 elevation contributes to B cell hyperactivity in SS patients. Treatment targeting IL-27 may be promising for the amelioration of this disease. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2416
Uterine Visualization on Tc-99m DTPA HSA Scintigraphy to Detect Gastrointestinal Protein Loss
Authors: KAZUYOSHI SUGA, YUKO ISHIKAWA, KAZUMI MOTOYAMA, NORIHIKO KUME, NAOFUMI MATSUNAGA
Journal: Clinical Nuclear Medicine (2000)

To detect the focus of intestinal protein loss, abdominal Tc-99m DTPA HSA scintigraphy was performed in a 41-year-old woman with diffuse eosinophilic enteritis and hypoalbuminemia. It was the first day of the menstrual phase of her menstrual cycle at the time of examination. The sequential images showed persistent, increasing radioactivity of the tracer above the urinary bladder during the examination. CTs and MRIs showed that the sites of uptake corresponded to the ovariouterine venous plexus and uterus. Three weeks later, a right ovariectomy was performed for a benign ovarian cyst, but no abnormality was found in the uterus. Uterine accumulation of the tracer during the menstrual or secretory phases of the menstrual cycle may cause a false-positive interpretation of Tc-99m DTPA HSA scintigraphy.
Abstract 3637: MM-302, a HER2-targeted liposomal doxorubicin, shows binding/uptake and efficacy in HER2 2+ cells and xenograft models
Authors: Stephan Klinz, Isabelle Eckelhofer, Daniel Gaddy, Elena Geretti, Bart Hendriks, Helen Lee, Shannon Leonard, Joe Reynolds, Tom Wickham
Journal: Cancer Research (2011)

Abstract Introduction: MM-302 is an ErbB2/HER2-targeted liposomal doxorubicin formulation designed to target doxorubicin to HER2-overexpressing cancer cells while limiting uptake into non-target cells. The characterization of the binding and uptake of MM-302 as a function of HER2 surface levels on various cell lines and in tumor models will help determine the minimum HER2 receptor levels required for MM-302 patient selection. Methods: Cellular models included 16+ established human tumor cell lines as well as 4T1 murine breast cancer and HeLa human cervical cancer cells engineered to overexpress HER2 from 1E05-1E06 receptors/cell. Cells were incubated with MM-302, untargeted liposomes or free doxorubicin and binding/uptake was measured by HPLC or flow cytometry. In vivo efficacy was determined in select mouse xenograft models. Tumors were mechanically and enzymatically dissociated, followed by flow cytometry to quantify the uptake of targeted and untargeted liposomes into HER2-expressing tumor cells, macrophages and other cell types. Results: Binding and uptake of MM-302 increased with rising HER2 surface levels in cells of common parental origin (4T1, HeLa), with significant uptake into cells with &amp;gt;2E05 HER2/cell. Further, total cell binding/uptake of MM-302 also increased with rising HER2 expression across a panel of 16+ cell lines. There was negligible uptake of untargeted liposomes under all conditions that showed no dependence on HER2 expression. Improved anti-tumor efficacy of MM-302 was observed in BT474-M3 and NCI-N87 mouse xenograft models relative to untargeted liposomal doxorubicin and free doxorubicin. Further, using disaggregated tumors, the relationship between HER2 expression and MM-302 uptake was confirmed in vivo in both models. Conclusions: Our studies identified a HER2 threshold for uptake of MM-302 of approximately 2E05 receptors/cell, and suggest a role for MM-302 not only in HER2 3+ cancers, but also in HER2 2+ cancers as well. The ability to treat HER2 2+ tumors offers an exciting opportunity to serve a major unmet clinical need. 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 3637. doi:10.1158/1538-7445.AM2011-3637
FRI0294 Feasibility of radiographic damage scores in ankylosing spondylitis
Authors: S. Ramiro, C. Stolwijk, A. van Tubergen, D. van der Heijde, R. Landewé
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Radiographic damage is one of the core outcomes in Ankylosing Spondylitis (AS) and it is usually assessed with the modified Stoke AS Spine Score (mSASSS). Another score has recently been proposed, the Radiographic AS Spinal Score (RASSS)[1], which includes an additional assessment of the lower thoracic vertebrae. However, so far no further application of this proposed score has been reported, neither with respect to its feasibility, nor confirming its additional value compared to the mSASSS. <h3>Objectives</h3> To assess the feasibility of mSASSS and RASSS. <h3>Methods</h3> Spinal radiographs from patients included in the Outcome in AS International Study (OASIS) were used. Cervical and lumbar spine radiographs were taken every 2 years during a period of 12 years. Two readers independently scored the x-rays, including all the vertebral corners (VCs) to be assessed according to both scoring methods. Scores per VC were averaged between the readers. A missing value for a VC was considered when both readers assessed it as missing; otherwise the score of one of the readers was used. Only radiographs from both cervical and lumbar spinal segments were included when available with ≤3 missing VCs per segment. In cases with ≤3 missing VCs, the missing VCs were recorded as needing to be imputed. The availability of the radiographs for the calculation of each of the scores was expressed in percentage of the total number of available radiographs. The availability of individual thoracic VCs added in the RASSS was also investigated. <h3>Results</h3> A total of 925 radiographs from the 217 patients initially included in OASIS were collected during the 12-year follow-up period. From those, 814 (88%) could be used for the mSASSS calculation and 637 (69%) for the RASSS calculation (both ≤3 missing VCs per spinal segment). In 177 out of 814 (22%) evaluable radiographs, all 4 additional thoracic VCs in the RASSS were missing, in 64 (8%) radiographs only 1 additional thoracic VC was available, and in 301 (37%) radiographs 2 additional thoracic VCs were available. In 365 out of 637 (57%) radiographs where the RASSS could be calculated, this could only be done based on 1 or 2 real scores from the 4 additional thoracic VCs, with the remaining missing VCs being imputed. These VCs were therefore uninformative. <h3>Conclusions</h3> The RASSS does not seem to be a suitable instrument to assess radiographic damage in AS. Its calculation is frequently impossible or strongly based on artificial scores. Even though, it might capture additional information not reflected in the mSASSS, it shows a poor feasibility, an important aspect of the OMERACT filter to be accounted for when assessing an outcome measure. <h3>References</h3> Baraliakos et al. Arthritis &amp; Rheumatism, 2009: 61, 764-771 <h3>Disclosure of Interest</h3> None Declared
Abstract 5352: Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation.
Authors: Orla M. Gannon, Lilia Merida de Long, Liliana Endo Munoz, Mehlika Hazar Rethinam, Nicholas Saunders
Journal: Cancer Research (2013)

Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers diagnosed worldwide and is associated with a 5-year survival rate of 55%. EZH2, a component of the polycomb repressor complex 2, trimethylates H3K27 (H3K27me3); which has been shown to drive squamous differentiation in normal keratinocytes. This study determined whether inhibition of EZH2-mediated epigenetic silencing could induce differentiation or provide therapeutic benefit in HNSCC. We determined the effects of inhibiting EZH2, by either RNA interference or pharmacologically, on HNSCC growth, viability and differentiation in vitro. Xenografts of HNSCC cell lines were used to assess efficacy of 3-Deazaneplanocin A (DZNep), an inhibitor of H3K27 trimethylation, in vivo. EZH2 was highly expressed in HNSCC cell lines in vitro and tissue microarray analysis revealed high expression in (n= 59) in situ relative to normal oral epithelium (n=12). Inhibition of EZH2 with siRNA could induce expression of differentiation genes in differentiation-refractory squamous cell carcinoma cell lines. Differentiation-refractory HNSCC cell lines displayed persistent H3K27me3 on the promoters of differentiation genes. DZNep caused cancer-cell specific apoptosis in addition to a profound reduction in colony forming efficiency and induction of some squamous differentiation genes. Furthermore, in vivo, DZNep attenuated tumour growth in two different xenograft models, caused intra-tumour inhibition of EZH2 and induction of differentiation genes in situ. Collectively, these data suggest that aberrant differentiation in HNSCC may be attributed to epigenetic dysregulation and suggests that inhibition of PRC2-mediated gene repression may represent a potential therapeutic target. Citation Format: Orla M. Gannon, Lilia Merida de Long, Liliana Endo Munoz, Mehlika Hazar Rethinam, Nicholas Saunders. Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2013-5352
SP0134 Refractory rheumatoid arthritis; all the therapeutic arrows spent?
Authors: A.P. Malaviya
Journal: Annals of the Rheumatic Diseases (2013)

45 year old female patient. Severe active refractory seropositive erosive rheumatoid arthritis. Failed treatment with the following conventional DMARDs: 1. Methotrexate 2. Leflunamide 3. Sulphasalazine 4. Myocrisin 5. Cyclosporin 6. Cyclophosphamide 7. Azathioprine 8. Mycophenolate Failed treatment with the following biologic DMARDs: 1. Infliximab 2. Etanercept 3. Adalimumab 4. Rituximab 5. Abatacept 6. Tocilizumab <h3>Disclosure of Interest</h3> None Declared
Case 26-2015
Authors: Jean E. Klig, Vandana L. Madhavan, Gleeson N. Rebello, Randheer Shailam
Journal: New England Journal of Medicine (2015)

A 9-month-old girl presented with a 2-month history of recurrent fevers. Examination revealed fever and tachycardia and was otherwise normal; chest and abdominal imaging studies showed no evidence of infection. Additional diagnostic tests were performed.
Validating CYP2D6 Genotype-Guided Tamoxifen Therapy for a Multiracial U.S. Population.
Authors: W. Irvin, L. Carey, E. Dees, L. Lange, W. Chiu, J. Evans, S. Anderson, K. Freidman, K. Weck, Z. Desta, C. Walko, O. Olajide, R. Raab, S. Corso, J. Peppercorn, D. Flockhart, H. McLeod
Journal: Cancer Research (2009)

Abstract Background: Tamoxifen is a selective estrogen receptor modulator that is the most commonly used and cost effective agent for hormone sensitive breast cancer with documented efficacy in prevention, treatment of preneoplasia, and treatment in both the adjuvant and metastatic settings. However, tamoxifen is a prodrug, and up to half of those taking it may not receive the full benefit because of genetic differences in CYP2D6 that affect metabolism to its active form, endoxifen. Tamoxifen is FDA approved for use at both 20mg/day and 40 mg/day, however by convention is dosed at 20mg. We aimed to determine if endoxifen levels can be manipulated by genotype-guided dosing of tamoxifen.Methods: 118 patients on tamoxifen ≥ 4 months and not on potent CYP2D6 inhibiting medications enrolled in Lineberger Comprehensive Cancer Center (LCCC) trial 0801. Genotyping was performed using the CYP450 Amplichip® (Roche Diagnostics) for 2D6 alleles: *1-11, *15, *17, *19, *20, *29, *35, *36, *40, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN and *41 XN. Tamoxifen dose was increased from 20mg to 40mg in patients with any intermediate or poor metabolizing (IM or PM) alleles [but not in patients homozygous for extensive metabolizing (EM) alleles]. Endoxifen levels were drawn at baseline and 4 months later. Assuming that endoxifen levels in IM pts are 40% lower than EM at baseline (Jin et al., 2005) and with a one-sided significance level of 0.025 and a sample size of 40 patients with intermediate metabolizing CYP2D6 genotypes, this study would have 84% power to detect a 40% increase in endoxifen.Results: Of the 118 patients, 25 withdrew or were removed from study, leaving 93 who have completed this study and who are evaluable for the primary analysis. Genotyping results were presented at 2009 ASCO meeting (Irvin et al.). For this analysis, 19 (20%) are African-American, 69 (74%) are non-Hispanic white, 2 are Hispanic, and 3 are Asian. For the 93 evauable patients, genotyping revealed 31 (33%) EM/EM, 1 EM/UM (ultra-rapid), 20 (22%) EM/IM, 19 (20%) EM/PM, 4 (4%) IM/IM, 9 (10%) IM/PM, 9 (10%) PM/PM and 1 unknown. The primary outcome, the tamoxifen metabolite levels, including endoxifen, will be available in July.(Supported by NC University Cancer Research Fund, NCI SPORE, Laboratory Corporation of America, Roche Diagnostics) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 410.
Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence
Authors: E.A. Mittendorf, A. Ardavanis, J. Symanowski, J.L. Murray, N.M. Shumway, J.K. Litton, D.F. Hale, S.A. Perez, E.A. Anastasopoulou, N.F. Pistamaltzian, S. Ponniah, C.N. Baxevanis, E. von Hofe, M. Papamichail, G.E. Peoples
Journal: Annals of Oncology (2016)
Acute Non-A–E Hepatitis in the United States and the Role of Hepatitis G Virus Infection
Authors: Miriam J. Alter, Margaret Gallagher, Timothy T. Morris, Linda A. Moyer, Emory L. Meeks, Krzysztof Krawczynski, Jungsuh P. Kim, Harold S. Margolis
Journal: New England Journal of Medicine (1997)

Little is known about the relation of the newly discovered hepatitis G virus (HGV) to the cause and clinical course of acute and chronic viral hepatitis.We selected patients from a surveillance study of acute viral hepatitis in four U.S. counties who had acute disease during 1985 to 1986 or 1991 to 1995. Serum samples were tested for HGV RNA by the polymerase chain reaction.HGV RNA was detected in 4 of 45 patients with a diagnosis of non-A-E hepatitis (9 percent), 23 of 116 patients with hepatitis C (20 percent), 25 of 100 patients with hepatitis A (25 percent), and 32 of 100 patients with hepatitis B (32 percent) (P<0.05 for the comparison of hepatitis B with hepatitis non-A-E or C). The clinical characteristics of the acute illness were similar for patients with HGV alone and those with hepatitis A, B, or C with or without HGV infection. During a follow-up period of one to nine years, chronic hepatitis did not develop in any of the patients with HGV alone, but 75 percent were persistently positive for HGV RNA, as were 87 percent of those with both hepatitis C and HGV infection. The rates of chronic hepatitis were similar in patients with hepatitis C alone (60 percent) and those with both hepatitis C and HGV infection (61 percent).The evidence from this surveillance study does not implicate HGV as an etiologic agent of non-A-E hepatitis. Persistent infection with HGV was common, but it did not lead to chronic disease and did not affect the clinical course in patients with hepatitis A, B, or C.
P4-09-14: Differential Expression of the Akt1 Isoform in Mammary Ductal Carcinoma.
Authors: AJ Sanders, RE Mansel, WG Jiang
Journal: Cancer Research (2011)

Abstract Introduction: AKT1 is an oncogenic protein and controls numerous cellular processes in both normal and cancerous cells. There are three isoforms, Akt1 (PKBα), Akt2 (PKBβ) and Akt3 (PKBγ). Frequently, regulation of the Akt pathway is disrupted in cancerous cells and interest within the scientific community has focused on the use of this pathway in treating cancer. However, recent studies have also implicated that Akt1 may act to limit invasive migration of breast cancer cells suggesting the potential of this isoform to have both pro- and anti- tumorigenic roles. In the current study we examined the expression profile of Akt1 in a cohort of ducal carcinoma of the breast. Methods: Quantitative transcript analysis was used to assess the expression levels of Akt1 in a range of ductal carcinoma of the breast (n=85) and normal samples. Expression levels were used in conjunction with clinical and pathological data, as well as the clinical outcomes of the patients (median follow-up 120 months). Results: Expression of Akt1 levels in the mammary ductal carcinoma cohort demonstrated a lower level of transcript expression in the lower grade and stage cancers. Levels of Akt1 were found to be significantly lower in grade 1 ductal breast carcinomas compared to the combined higher grade 1 and 2 carcinomas (ductal carcinoma grade 1 median = 3.7 vs ductal carcinoma grade 2,3 median = 33.6, p = 0.01). In addition to this, median transcript levels of Akt1 were found to increase with increasing TNM stage of the ductal carcinoma (Median values of Akt1 in ductal carcinoma TNM 1 = 5.9, TNM 2 = 63.6, TNM 3 = 533 and TNM 4 = 13680). This enhanced expression of Akt1 in higher TNM stages, compared to TNM stage 1, was found to be significant in most cases (TNM1 vs TNM2, p = 0.03; TNM1 vs TNM3, p = 0.15; TNM1 vs TNM4, p = 0.03). Conclusion: Variable expression of Akt1 was seen throughout the mammary ductal carcinoma cohort and correlated with a number of prognostic factors. Akt1 transcript levels were found to be significantly reduced in the low grade 1 and TNM1 stages when compared to the higher grades and TNM stages. Our current data suggests that low levels of Akt1 may be associated with better clinical patient prognosis in mammary ductal carcinoma. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-14.
German politician and psychiatrist face manslaughter charges for their role in assisted suicide deaths
Authors: N. Stafford
Journal: BMJ (2014)

Prosecutors in Hamburg, Germany, have charged a politician and a psychiatrist with manslaughter after the deaths of two elderly women from assisted suicide in 2012. If convicted, both men could face five years to life in prison.

In a press statement prosecutors in Hamburg identified one of the accused as Roger Kusch, an outspoken advocate of assisted suicide and former justice senator for Hamburg, one of Germany’s 16 federal states. Kusch, now chairman of Sterbehilfe Deutschland (Assisted Suicide Germany), triggered global headlines …