tbuckley/cabot-search huggingface dataset:
Abstract 796: Impact of histological types on infiltration of regulatory T cells in gastric cancer
Authors: Mami Yoshii, Hiroaki Tanaka, Katsunobu Sakurai, Hisashi Nagahara, Kenjirou Kimura, Ryousuke Amano, Eiji Noda, Naoshi Kubo, Kazuya Muguruma, Nobuya Yamada, Masakazu Yashiro, Kiyoshi Maeda, Tetsuji Sawada, Masaichi Ohira, Tetsurou Ishikawa, Kosei Hirakawa
Journal: Cancer Research (2011)

Abstract Introduction: It is recently known that regulatory T cells (Tregs) are naturally present in the immune system and play important roles of suppression in host's antitumoural immune response. The transcription factor forkhead box P3 (FoxP3) is the most reliable marker for Tregs, and involved in the development and function of Tregs. Previous studies have pointed out that increasing of Tregs were associated with progression of many solid cancers such as breast cancer, melanoma, head and neck cancer, esophageal cancer. However, few reports were found about gastric cancer. Signet ring cell carcinoma with more advanced stage increase the risk of metastasis, like scirrhous carcinoma. It is uuclear whether the number of Tregs is correlated with the progression of signet ring cell carcinoma. The aim of this study is to investigate the population of tumor infiltrating Tregs and the impact of histological types on that in gastric cancer. Materials and methods: A total of 100 patients with gastric cancer who underwent gastrectomy between 2003 and 2008 at our institute were enrolled. FoxP3 expression in primary gastric cancer was analyzed by immunohistochemistry. T cells expressed FoxP3 were defined as Tregs. Results: Our cohort of 100 patitents included almost all histological types of gastric cancer, including tubular adenocarcinoma, poorly differentiated adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, squamous cell carcinoma, and signet ring cell carcinoma. We detected FoxP3 expression in more than 90% of primary tumors. FoxP3 positive cells infiltrating into tumor were considered as Tregs. The localization of observed infiltrating Tregs expanded to not only tumor but also regional lymph node. The number of Tregs in tumor increased according to the differentiation of the cancer cells. Importantly, we detected significant few tumor infiltrating Tregs in signet ring cell carcinoma compared with the other histological types. On the other hand, signet ring cells themselves expressed FoxP3, indicating that signet ring cells might play a role of suppression of immune response to cancer. Conclusion: We have observed that there were differences between signet ring cell carcinoma and other histological types with regard to the distribution of FoxP3 expression cells. Although the detail clinical investigation is needed, our result suggested that taylor made arrangement associated with histological types should be required for immunotherapy against gastric 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 796. doi:10.1158/1538-7445.AM2011-796
FRI0315 Congenital heart block in a cohort of pregnant women with anti-ro/ssa and/or anti-la/ssb antibodies.
Authors: S. M. Palasti, V. Dominguez, N. Masoller, J. C. Ramirez, I. Teixido, R. Cervera, F. Figueras, G. Espinosa
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Maternal autoimmune-mediated fetal heart disorders include a wide spectrum of conduction disturbances that can appear in fetuses of pregnant women with systemic autoimmune diseases, being congenital heart block (CHB) one of the most common and severe manifestations. The pathogenic role of maternal anti-Ro/SSA and anti-La/SSB antibodies has been well established in several studies. <h3>Objectives</h3> To describe the characteristics of maternal autoimmune-mediated fetal heart disorders in a cohort of pregnant women with anti-Ro/SSA and/or anti-La/SSB antibodies from an Autoimmune Diseases Pregnancy Clinic of a tertiary hospital. <h3>Methods</h3> We conducted a retrospective study to describe the prevalence of maternal anti-Ro/SSA and anti-La/SSB antibodies and their relationship with fetal heart disorders in pregnant women referred to our Autoimmune Diseases Pregnancy Clinic from1<sup>st</sup> January 2009 to 31<sup>st</sup>of December 2012. <h3>Results</h3> A total of 133 pregnant women were referred to our clinic. The mean (SD) age was 35 (5.2) years and 123 (94%) were Caucasian. 63 (49%) women had SLE, 26 (20%) primary antiphospholipid syndrome, 11 (8%) primary Sjögren Syndrome (SS), 30 (22%) had other systemic autoimmune diseases and 3 (1%) were asymptomatic carriers of autoantibodies. Anti-Ro/SSA and/or anti-La/SSB antibodies were detected in 48 (36%) of these pregnant women: 47 (35%) had anti-Ro/SSA and 29 (22%) anti-La/SSB antibodies (both autoantibodies were detected in 26 (20%) women). CHB was detected by fetal echocardiography in 5 fetuses: Complete CHB (third degree) in three fetuses and second-degree CHB in the other two. The mean (SD) gestational age at the time of CHB detection was 21.8 (2.1) weeks. Four women were positive for anti-Ro/SSA and anti-La/SSB antibodies and the remaining was positive for anti-Ro/SSA. Three mothers were asymptomatic carriers of these antibodies and two had primary SS. Two women presented CHB in previous pregnancies; one was an asymptomatic carrier of anti-Ro/SSA and anti-La/SSB antibodies and the other had primary SS, respectively. Regarding fetal outcomes, the two women with second-degree CHB received dexamethasone and the newborns did not require any intervention. Among newborns with complete CHB, one needed a perinatal pacemaker implantation; one suffered an intrauterine fetal death and in the remaining the pregnancy was interrupted after the diagnosis of hydrops. <h3>Conclusions</h3> All mothers of the fetuses with CHB from our cohort presented anti-Ro/SSA antibodies. They represented 10.6 % of the pregnant women with anti-Ro/SSA antibodies. Fetal echocardiography allowed the prenatal diagnosis and guided the management of the disease. Early serological and ultrasound screening is strongly recommended to recognize CHB in pregnant women with these antibodies. <b>Disclosure of Interest</b>: None Declared
Abstract 5283: A role for mitochondrial derived reactive oxygen species in regulating pro-migratory signaling pathways via p130cas
Authors: Nadine Hempel, J. Andres Melendez
Journal: Cancer Research (2010)

Abstract A cell's migratory and invasive potential depends on a multitude of signaling pathways, which present novel targets for anti-cancer therapies. We and others have shown that reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), are modulators of tumorigenicity and contribute to the migratory phenotype of cancer cells (Connor et al. 2008, Cancer Research). Intrinsic levels of ROS are elevated in numerous metastatic cancer types, which suggests that these cells have evolved to utilize sublethal increases in ROS levels as novel second messengers in regulating pro-metastatic signaling events. Here we present evidence to support this hypothesis and describe how ROS may act as second messengers in the Focal Adhesion Kinase (FAK) pathway. Cells displaying intrinsic picomolar changes in H2O2 levels, either endogenously (metastatic 253J-BV bladder cancer cell line, compared to its non-metastatic parental 253J-P line), or as a consequence of enforced mitochondrial manganese superoxide dismutase (Sod2) expression, display an enhanced migratory phenotype. This is accompanied by a loss of mature vinculin positive focal adhesions. Mechanistically, we show that the protein tyrosine phosphatases PTP-PEST and PTEN are oxidized and inactivated in cells displaying enhanced H2O2 levels and that this can be reversed by effective removal of H2O2 following expression of the H2O2 detoxifying enzyme catalase (CAT). A consequence of PTP-PEST oxidation and inactivation is a concomitant increase in phosphorylation of its primary substrate p130cas, an adaptor protein of the FAK signaling cascade. Further, increases in intracellular H2O2 levels shift the localization of p130cas to the cell surface, as assessed by membrane/cytoskeletal fractionation and immunofluorescent staining, indicative of localized activation of FAK pathway signaling at the leading edge. Again co-expression of CAT negates these effects, indicating that these mechanisms are H2O2 dependent. The data described support the hypothesis that elevated mitochondrial ROS levels can regulate the spatial activation of pro-migratory signaling pathways, enhancing the metastatic potential of cancer cells. 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 5283.
PTU-084 Incidental gallbladder cancer after laparoscopic cholecystectomy: treatment and surveillance policies in the UK: result of a survey
Authors: G Marangoni, A Hakeem, G J Toogood, J P A Lodge, R K Prasad
Journal: Gut (2012)

<h3>Introduction</h3> Increasingly diagnosis of early gallbladder cancer (GBC) is incidentally made after laparoscopic cholecystectomy (LC). T stage correlates with nodal metastases and potential for residual disease. Although there is no controversy in the treatment of T1a and T2 tumours, there is still no agreement on what constitutes optimal management for pT1b and the extent of lymphadenectomy for pT2 tumours. Staging, timing of surgery after LC and treatment of the extrahepatic biliary tree are not standardised. <h3>Methods</h3> The aim of this study was to assess the treatment, staging and surveillance protocols of incidentally found GBC after LC among hepatobiliary and upper GI surgeons in the UK in the light of the current published literature. A questionnaire on incidental GBC was devised and sent to the Consultant Surgeons members of the Association of Upper GI Surgeons of Great Britain and Ireland after approval from the Association of Upper GI Surgeons Committee. There were 13 questions regarding treatment protocols according to T category (pT1a/pT1b, pT2), treatment of previous port sites, staging protocols, surveillance policies, timing of surgery after LC, extent of lymphadenectomy and management of the extrahepatic biliary tree. <h3>Results</h3> There were 48 completed questionnaire. Over 80% would consider simple LC an adequate treatment for T1a tumours. 30% do not advocate radical surgery for T1b and 50% would not perform regional lymphadenectomy. 5% would not further treat T2 tumours and 23% would not add regional lymphadenectomy. Over 50% would not resect port sites. About 50% would consider chest and abdomen CT only for staging. About 30% and 80% would recommend surveillance for CT or MRI for 2–5 years for T1 and T2 tumours after extended resection respectively. 72% would advocate surgery as soon as possible. 22.5% and 20% would perform coeliac trunk lymphadenectomy if staging confirms positive nodes and routinely excise the extrahepatic biliary tree respectively. <h3>Conclusion</h3> The only chance of cure for GBC is complete tumour excision. There is heterogeneity among UK surgeons regarding treatment, staging and surveillance policies. According to the survey, UK practice does not fully comply with published evidence for T1a and T2 categories. Although there is increased evidence that T1b tumours would benefit from extended resection only 50% would perform a regional lymphnode dissection. Clear guidelines would help standardisation of staging and surveillance policies. <h3>Competing interests</h3> None declared.
MB-24 * SILAC BASED QUANTITATIVE PROTEOMICS OF MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: J. Staal, L. S. Lau, H. Zhang, Y. Hathout, K. Brown, B. Rood
Journal: Neuro-Oncology (2015)

Despite landmark advances in the genomics of medulloblastoma, significant ambiguity exists in the translation these findings into therapeutic advances.We propose that quantitative proteomics can be used to better discern driver aberrations and more directly view the functional, and therefore targetable, biology of this disease.METHODS: We created a Stable isotope Labeling of Amino acids in cell Culture (SILAC) reference atlas of proteins from 4 medulloblastoma cell lines and spiked it into cell lysates of low passage medulloblastoma cultures.A Hybrid LTQ-Orbitrap mass spectrometer was used to quantitate proteins relative to the atlas.RESULTS AND DISCUSSION: We used the SILAC reference atlas to quantitate the proteome of myc-amplified and non-myc-amplified group 3 low passage medulloblastoma cells.Accurate quantitation was achieved for an average of 1215 proteins per primary cell line.Technical replicates resulted in r 2 values between 0.91 and 0.98.The differentially abundant proteins myc-amplified tumors reveal protein-protein connectivity networks associated with alternative splicing, ribosome biogenesis and metabolism.At the junction of splicing and metabolism, we confirmed the upregulation of specific splicing factors (HNRNPs) in the myc-amplified group.We demonstrate the HNRNP control of PKM isoform generation and the subsequent effect upon tumor cell metabolism and resistance to hypoxia.Furthermore, we confirm these proteomic findings using independent medulloblastoma tissue samples and show they are conserved in low passage primary tumor cultures.CONCLUSIONS: Our results demonstrate the advantages of quantitative proteomic profiling to discover oncogenic driver molecules.This is particularly significant given the emerging evidence of the poor correlation between mRNA abundance and protein abundance.Ultimately, insight into the protein level biology provided by these types of studies will yield more readily accessible therapeutic targets and allow clearer inferences of disease biology.
P62 Immunological analysis and clinical profile of Chronic Hepatitis B Virus (HBV) infection in the younger patient
Authors: P. T. F. Kennedy, E. Sandalova, J. Jo, U. S. Gill, L. Li, I. Ushiro-Lumb, S. Naik, G. R. Foster, A. Bertoletti
Journal: Gut (2011)

<h3>Introduction</h3> Establishing disease phase in chronic HBV is a critical step in long-term disease management. This classification has even more significance at a younger age, where a proportion of eAg positive patients are labelled ‘immune tolerant’ and treatment is deferred. However, disease phase is diagnosed on clinical phenotype only with little insight into immunological activity. <h3>Aim</h3> The aim of this study was to investigate the immunological profile in HBV infected children and young adults across different phases of disease and to compare the HBV-specific responses detected with those of older HBV infected patients. <h3>Method</h3> 45 children and young adults (median age 19, range 12–30) were recruited and followed longitudinally for a minimum of 12 months. Clinical profile included ALT, HBV DNA, quantitative HBsAg and, where available, biopsy fibrosis stage and NI scores. This was compared with the immunological analysis for each subject comprising: global T cell cytokine profile (frequency of T cells producing IFNα, IL-2, IL-4, TNFα and the ILs; 17, 8, 21, 22 and MIP-1a after PMA stimulation), quantity of T cells (CD4 and CD8) expressing exhaustion markers (PD-1, Lag-3, CTTL-4) and the presence of functional HBV-specific T cells (PBMC stimulated with overlapping HBV peptides covering envelope, core and E proteins). <h3>Results</h3> Frequency of T cells producing immunosuppressive or Th2 cytokines (IL-10, IL-4) and (IL-8, IL-21) is similar between age matched HBV infected and non-infected young adults, while T cells with pro-inflammatory cytokines (IFNα, TNFα, IL-17) were increased in the HBV infected group (p≤0.05). In addition, IL-22 producing cells were present in HBV infected young adults while almost absent in age matched uninfected controls. T cells expressing exhaustion markers were increased in HBV infected patients irrespective of age and correlated with ALT activity. Contrary to predictions HBV-specific T cells were detected with greater frequency in younger HBV-infected subjects when compared with those found in older infected patients (p≤0.05). The HBV-specific T cell response in younger patients show a classical Th1/Tc1 cytokine production profile and expands more vigorously than that seen in older HBV patients. <h3>Conclusion</h3> HBV infection in young patients did not induce a generic immune tolerant T cell cytokine profile. On the contrary, disease activity in chronic HBV appears to be independent of age. Furthermore, the detection of HBV-specific T cells and the presence of significant liver damage on biopsy in a proportion of our young adult patients underlines the dangers of labelling these patients as ‘immune tolerant’. Our findings highlight the dynamic nature of chronic HBV and stress the importance of more formal disease assessment in children and young adults with early therapeutic intervention where indicated.
Abstract 3267: Bortezomib sensitizes human acute myeloid leukemia cells to all-trans-retinoic acid-induced differentiation by modifying the RARα/STAT1 axis.
Authors: Meidan Ying, Lei Zhang, Like Zhong, Xuejing Shao, Peihua Luo, Xiaochun Yang, Bo Yang, Qiaojun He
Journal: Cancer Research (2013)

Abstract All-Trans-Retinoic Acid (ATRA) has held great promise for differentiation-based therapy, but reportedly down-regulates retinoic acid receptor alpha (RARα) in a proteasome-dependent manner, which leads to decreased AML cell differentiation efficiency. Therefore, research strategies that seek to further sensitize cells to retinoids and extend the range of retinoid-affected myeloid malignancies beyond APL are key investigative avenues. Here, we demonstrate that bortezomib, the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma, exhibited strong synergism with ATRA to promote HL60 and NB4 AML cell differentiation. We observed that bortezomib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation, without cell death. Additionally, treatment of human leukemia HL60 xenografts with bortezomib and ATRA together did not increase bortezomib-induced progressive weight loss but resulted in significant tumor growth inhibition in addition to increased differentiation (p&amp;lt;0.05). These enhanced differentiation effects were accompanied by RARα stabilization and STAT1 activation. Taken together, our study was the first to evaluate bortezomib and ATRA synergy in AML cell differentiation and to assess new opportunities for bortezomib and ATRA combination as a promising approach for future differentiation therapy. Citation Format: Meidan Ying, Lei Zhang, Like Zhong, Xuejing Shao, Peihua Luo, Xiaochun Yang, Bo Yang, Qiaojun He. Bortezomib sensitizes human acute myeloid leukemia cells to all-trans-retinoic acid-induced differentiation by modifying the RARα/STAT1 axis. [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 3267. doi:10.1158/1538-7445.AM2013-3267 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
PWE-244 Does thromboprophylaxis in ulcerative colitis work?: data from the UK IBD audit
Authors: R W Lynch, M Roughton, C Down, I D Arnott
Journal: Gut (2012)

<h3>Introduction</h3> Venous thromboembolism (VTE) has been long recognised as a complication of inflammatory bowel disease (IBD) with prevalence being reported at between 1.25 and 6.7% and a threefold increased risk being reported when compared to matched cohorts. It has led to recommendations that all patients admitted with acute flares of ulcerative colitis should be given prophylactic subcutaneous heparin although data of efficacy in an IBD population are lacking. We aim to assess the incidence, prophylaxis and possible aetiology of VTE in ulcerative colitis. <h3>Methods</h3> We audited 3049 patients with UC. Median age was 42; there were 1421 females and 1628 males. 495 admissions were for elective surgery and there were 2504 emergency admissions of which 882 were considered to have severe disease. 202 Sites audited a median of 18 UC patients per site that were admitted with IBD between 1 September 2009 and 31 August 2010. Data collected contained specific questions on the administration of subcutaneous heparin and whether the patient had a thrombotic event during their admission. We also assessed whether type of admission, age, co-morbidities, disease severity, surgical operations, gender, steroid therapy and treatment response were related to VTE. <h3>Results</h3> Of the 3049 patients admitted with ulcerative colitis, 2668 (87.5%) patients were given prophylactic heparin. 66 (2.2%) patients experienced thrombotic events during their admission. The rate of VTE among heparinised patients, 2.2% (59/2668), did not differ significantly when compared to a rate of 1.8% (7/381) within the population who didn9t receive prophylaxis (p&lt;0.8). VTE was associated with the need for surgery: 39.4% (26/66) of patients with VTE underwent surgery compared with surgery in 26.2% (781/2983) without VTE (p&lt;0.02). Of these 26 surgical patients within the VTE population, four of these patients9 VTE were post-operative. When patients undergoing elective surgery are excluded VTE is associated with co-morbidity: 46.0% (23/50) of the VTE population compared to 32.4% (810/2504) in the non-VTE population (p&lt;0.03). There was no association of VTE with disease severity (severe disease in 42.0% (21/50) with DVT vs 34.4% (861/2504) without VTE, p&lt;0.3) or the use of steroids (steroids used in 96.0% (48/50) with VTE vs 89.6%% (2244/2504) without VTE, p&lt;0.08). <h3>Conclusion</h3> Although there was no difference in the frequency of VTE in patients given or not given heparin the numbers of VTE within this group are small. This analysis does however demonstrate that patients with co-morbidity and those undergoing surgery are at higher risk of VTE. Additional measures to prevent VTE should be considered in these patients such as a combination of heparin and compression stockings. All IBD patients admitted to hospital should continue to receive prophylactic subcutaneous heparin. <h3>Competing interests</h3> None declared.