tbuckley/cabot-search huggingface dataset:
P3-18-03: In Vitro Potency of mTOR Kinase (TOR1/TOR2) Inhibitor, INK128 in ER+ and HER2 Overexpressing Breast Cancer Cells.
Authors: P De, Y Sun, N Dey, B Leyland-Jones
Journal: Cancer Research (2011)

Abstract Background Persistent activation of the PI3K-AKT-mTOR1/2 signaling pathway drives aberrant cell growth and proliferation in a variety of tumor types including breast tumors. Recent works have demonstrated a strong association between mutational activation of PIK3CA or loss of function of PTEN and resistance to therapies targeted against the ER or HER2 pathway. Purpose: Since PI3K-AKT-mTOR is one of the major signaling pathways responsible for the progression of breast cancer, as well as appears to be upregulated during development of the resistance to the endocrine and trastuzumab treatment, suppression of this pathway by administration of INK128 (mTOR1/2 kinase inhibitor) may therefore be efficacious in ER+ and HER2+ breast cancer models. Experimental Design: To examine this possibility, INK128 was treated in ER+ (MCF7, BT483, T47D and MDA-MB-415), trastuzumab-sensitive HER2+ (BT474), trastuzumab-resistant (BT474HR), and PIK3CA mutated/HER2+ breast cancer cells (HCC1954 and UACC893). We have tested the effects of INK128 on the, (a) cell survival/proliferation, (b) integrin-directed cell migration, and small GTP-ase activation, (c) downstream signaling pathways for proliferation and apoptosis, and (d) 3D ON-TOP-colony formation. Results: Treatment of ER+ and HER2+ cell lines with INK128 in vitro showed that 1) cell lines were sensitive to single agent INK128 with 50% inhibitory concentration ranging from 15 nM-10 μM in ER+ cell lines and 20 nM −50 nM in HER2+ cell lines, 2) 70–80% anti-proliferative activities were observed on 3D-ON TOP colony formation assay in both ER+ and HER2+ cells, 3) INK128 dose- and time-dependently blocked downstream effectors of mTOR1/2 pathway i.e. p-AKT (at Ser473), p-P70S6K, p-S6 ribosomal protein, p-4EBP1(interestingly, potent inhibition was also observed in cell line resistant to trastuzumab), 4) INK128 also blocked AKT phosphorylation at Thr308 (although in lesser extent than at Ser473), 5) rapalog-mediated AKT activation was blocked when cells were treated with INK128, 6) in ER+ cell lines INK128 more efficiently blocked p-4EBP1 than rapalog, 7) HER3 expression was significantly upregulated following treatment of trastuzumab-resistant cells (BT474HR) with INK128, and 8) integrin-dependent cell migration was significantly abrogated with INK128 in association with inhibition of RAC1-GTP. Conclusion: Our preclinical in vitro data demonstrate that concurrent inhibition of mTOR1and mTOR2 is likely to be a more effective in both ER+ and HER2+ breast cancer cells than the inhibition of mTOR1 alone. We are currently studying the effect of INK128 on downstream apoptotic signals in ER+ and HER2+ cell lines, the results of which will be presented in the meeting. INK128 was generously supplied by Inkellikine, San Diego, CA. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-18-03.
Abstract 3962: Knocked down miR-221/222 inhibits Akt pathway to suppress malignant glioma cell growth independent of PTEN status
Authors: Chunzhi Zhang, Anling Zhang, Jianwei Hao, Junxia Zhang, Zhifan Jia, Guangxiu Wang, Peiyu Pu, Chunsheng Kang
Journal: Cancer Research (2011)

Abstract MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression after transcription. By base-pairing with the complementary sites in the 3’untranslated region (3’UTR) of the mRNA, miRNAs control mRNA stability and translation efficiency. Aberrant expression of miRNAs have been shown to be involved in tumorigenesis. MiR-221 and miR-222 were frequently overexpressed in human malignant tumor, including glioblastoma. By Northern Blot assay, we found that miR-221 and miR-222 upregulated in glioma cell lines. In addition, Akt pathway is aberrant activity in glioblastoma. Our work have proved that miR-221/222 promote malignant progression of glioma cell through activation of the Akt pathway. Once Akt activated, it promotes cellular proliferation and invasion ability and reduces cell apoptosis and radiosensitivity. By bioinformation analysis, we found that PTEN is a target of miR-221 and miR-222. By luciferase report assay, we identified that PTEN is a target of miR-221 and miR-222. It is unknown whether miR-221/222 activate Akt pathway dependent of PTEN status or not. We knocked down miR-221/222 with a specific antisense oligonucleotide and found that phenotype of glioblastoma cell changed in vitro in U251 (PTEN mutant) and LN229 (PTEN wild type), including increasing cell proliferation and invasion ability, reducing cell apoptosis and radiosensitivity. By Western Blot, knocked down miR-221/222-cells showed a decreased expression of EGFR, activated Akt, cyclin D, and Bcl-2. Furthermore, knockeddown miR-221/222 considerably decreased tumor growth in U251 cell xenograft model. By immunofluorescence assay, it was found that antisense-miR-221/222 significantly knocked down miR-221 and miR-222 in vivo. By Tunnel assay, antisense-miR-221/222 significantly increased cell apoptosis in vivo. By immunohistochemistry staining, some protein expression reduced, including expression of EGFR, activated Akt, cyclin D, and Bcl-2. Although miR-221 /222 is known to regulate PTEN and downregulation of miR-221/222 led to increased PTEN expression endogenously, the GBM suppressor effect of antisense-miR-221/222 is most likely independent of PTEN regulation because U251 has mutant PTEN. Taken together, our studies provide evidence that miR-221/222 may serve as a novel therapeutic target for malignant gliomas independent of PTEN status. 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 3962. doi:10.1158/1538-7445.AM2011-3962
Effectiveness of seasonal influenza vaccine in preventing influenza primary care visits and hospitalisation in Auckland, New Zealand in 2015: interim estimates
Authors: A Bissielo, N Pierse, QS Huang, MG Thompson, H Kelly, VP Mishin, N Turner
Journal: Eurosurveillance (2016)

Preliminary results for influenza vaccine effectiveness (VE) against acute respiratory illness with circulating laboratory-confirmed influenza viruses in New Zealand from 27 April to 26 September 2015, using a case test-negative design were 36% (95% confidence interval (CI): 11-54) for general practice encounters and 50% (95% CI: 20-68) for hospitalisations. VE against hospitalised influenza A(H3N2) illnesses was moderate at 53% (95% CI: 6-76) but improved compared with previous seasons.
Senior house officer exchange to Belgium
Authors: K. Darling
Journal: BMJ (1998)

Since 1975, a European Economic Community directive has allowed the free circulation of certain professionals within member states. This legislature enables recognition of primary qualifications so that doctors can gain full registration in any European Union member state without having to resit local examinations, provided that they are citizens of a member state and have trained within the European Union. Despite such freedom to circulate, however, British doctors remain hesitant. There are two main factors that make the English Channel as much a psychological as a physical barrier: finding a job and practising in a foreign language.

In 1977 a European exchange scheme was established between leading academic departments in Britain, Belgium, and Switzerland.(1) The goal was to further medical education by exposing junior doctors to different healthcare systems and cultures. Senior house officers, or the mainland European equivalent, were chosen from teaching hospitals involved in the scheme. At the time, the exchange was somewhat experimental, but was made possible with the help of the European Commission.(2)

Twenty years and nearly 200 candidates later, the scheme has proved successful, with exchanges taking place between 14 departments of medicine from eight countries.(3) Centres in Britain, Belgium, and the Netherlands have been the most active, but exchanges have also occurred in France, Germany, Switzerland, Austria, and Portugal.

Each post is arranged, usually annually, between the heads of the relevant centres, and candidates must apply in their native country. For British candidates, such appointments (for periods of 6-12 months) are advertised in the classified section of the BMJ, usually as part of a two year senior house officer rotation, in such centres as the Hammersmith, St Bartholomew's, Addenbrookes, and Guy's hospitals. Others are also starting to take part. If a candidate is well motivated and two heads of department …
Cystic pancreatic neuroendocrine tumors: endoscopic ultrasound and fine-needle aspiration characteristics
Authors: W. Yoon, E. Daglilar, M. Pitman, W. Brugge
Journal: Endoscopy (2013)

<b>Background and study aims:</b> Limited data are available on the endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) characteristics of cystic pancreatic neuroendocrine tumors (CPanNets). The aims of this study were to describe the EUS and FNA characteristics of pathologically confirmed CPanNets and to compare these characteristics with mucinous cysts from matched patients. <b>Patients and methods:</b> From an EUS – FNA database (between 1999 and 2011), 19 patients with a pathologically confirmed CPanNet were identified. Patient characteristics, cyst fluid carcinoembryonic antigen (CEA) levels, pathology, and EUS findings were analyzed. For comparison, age- and sex-matched patients with mucinous cysts were randomly chosen from the same database. <b>Results:</b> Of the 19 patients, two had multiple endocrine neoplasia type 1 and two had metastases. The median diameter of the lesions was 24 mm. EUS revealed unilocular lesions in 7 patients, thinly septated lesions with thin walls in 1, and mixed solid-cystic lesions in 11. EUS – FNA cytology confirmed neoplasm in 12 of the 19 patients (63.2 %). The median cyst fluid CEA level (n = 15) was 1.1 ng/mL (range 0.3 – 500 ng/mL). Compared with matched patients with mucinous cysts, the median cyst fluid CEA was lower (1.1 ng/mL vs. 400 ng/mL), thick walls were more common (66.7 % vs. 13.3 %), and diagnostic cytology was more likely (73.3 % vs. 20.0 %). <b>Conclusions:</b> Analysis of EUS and FNA results showed that the cyst fluid from CPanNets had a lower CEA concentration, a higher frequency of thick walls on EUS, and higher diagnostic cytology compared with mucinous cysts. These findings may aid in the diagnosis of CPanNets.
Effect of HLA Compatibility on Engraftment of Bone Marrow Transplants in Patients with Leukemia or Lymphoma
Authors: C Anasetti, D Amos, P G Beatty, F R Appelbaum, W Bensinger, C D Buckner, R Clift, K Doney, P J Martin, E Mickelson
Journal: New England Journal of Medicine (1989)

We analyzed the relevance of HLA compatibility to sustained marrow engraftment in 269 patients with hematologic neoplasms who underwent bone marrow transplantations. Each patient received marrow from a family member who shared one HLA haplotype with the patient but differed to a variable degree for the HLA-A, B, and D antigens of the haplotype not shared. These 269 patients were compared with 930 patients who received marrow from siblings with identical HLA genotypes. All patients were treated with cyclophosphamide and total-body irradiation followed by the infusion of unmodified donor marrow cells. The rate of graft failure was 12.3 percent among the recipients of marrow from a donor with only one identical haplotype, as compared with 2.0 percent among recipients of marrow from a sibling with the same HLA genotype (both haplotypes inherited from the same parents) (P less than 0.0001). The incidence of graft failure correlated with the degree of donor HLA incompatibility. Graft failure occurred in 3 of 43 transplants (7 percent) from donors who were phenotypically HLA-matched with their recipient (haplotypes similar, but not inherited from the same parents), in 11 of 121 donors (9 percent) incompatible for one HLA locus, in 18 of 86 (21 percent) incompatible for two loci, and in 1 of 19 (5 percent) incompatible for three loci (P = 0.028). In a multivariate binary logistic regression analysis, independent risk factors associated with graft failure were donor incompatibility for HLA-B and D (relative risk = 2.1; 95 percent confidence interval, 1.7 to 2.5; P = 0.0004) and a positive crossmatch for anti-donor lymphocytotoxic antibody (relative risk = 2.3; 95 percent confidence interval, 1.8 to 2.8; P = 0.0038). Residual host lymphocytes were detected in 11 of 14 patients with graft failure, suggesting that the mechanism for graft failure could be host-mediated immune rejection. We conclude that donor HLA incompatibility and prior alloimmunization are significant risk factors for graft failure, and that a more effective immunosuppressive regimen than those currently used is needed for consistent achievement of sustained engraftment of marrow transplanted from donors who are not HLA-identical siblings.
A8.1 Alarmins S100A8/A9 Cause Osteophyte Formation in Experimental Osteoarthritis with High Synovial Involvement
Authors: Rik FP Schelbergen, AB Blom, W de Munter, A Sloetjes, T Vogl, J Roth, WB van den Berg, PLEM van Lent
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Osteophyte formation is an important hallmark of osteoarthritis (OA) causing limited joint movement and pain. There is increasing belief that synovial activation contributes to OA pathology. As shown recently in our lab, alarmins S100A8 and S100A9 (major products of synovial macrophages) are involved in cartilage degradation and synovial activation during human and murine OA. In the current study, we explored the involvement of S100A8/A9 in osteophyte formation in experimental OA. <h3>Methods</h3> Experimental OA was elicited in C57Bl/6 (WT) mice and S100A9<sup>-/-</sup> mice, which also lack functional S100A8. Collagenase induced OA (CIOA) was induced by two times intra-articular injection of 1U collagenase, DMM was induced by transsection of the medial anterior meniscotibial ligament leading to destabilisation of the medial meniscus (DMM). Osteophyte size was assessed by a blind observer using Leica Application Suite (LAS) imaging software. Chondrogenesis was induced by bringing human foetal mesenchymal stem cells (MSCs) in pellet and stimulating for 5 days with BMP-2 and TGFβ1, with or without human recombinant S100A8. Proteoglycan content was quantified using the LAS imaging software on SafO stained sections. <h3>Results</h3> First, we measured osteophyte size in S100A9<sup>-/-</sup> mice at day 42 of CIOA. Synovial activation is high in CIOA and this is significantly reduced in S100A9<sup>-/-</sup> mice. Osteophyte size was dramatically reduced in the S100A9<sup>-/-</sup> compared to WT in the medial collateral ligament (92.5% reduction) but also significantly at the medial side of both tibia and femur (68.2% and 64.6% reduction) (n = 10). One explanation for the reduced osteophyte size in S100A9<sup>-/-</sup> mice may be a direct effect of S100-proteins on chondrogenesis. To investigate this, we stimulated MSCs in pellet culture with BMP-2 and TGFβ1, supplemented with 1 and 5 µg/ml S100A8. Proteoglycan deposition as measured by redness in SafO staining was increased 27% and 71% respectively, indicating that S100A8 stimulates chondrogenesis. Finally, we determined osteophyte size in the DMM model, in which synovial involvement is very low. At day 56, we observed no significant differences in osteophyte size between the S100A9<sup>-/-</sup> and WT at the medial femur and tibia (105% and 136% of WT, n = 8). This confirms the importance of the synovium in the S100-effect on osteophyte development. <h3>Conclusions</h3> S100A8/S100A9 play a crucial role in osteophyte formation in an OA model that shows clear synovial involvement, probably by stimulating chondrogenesis. Considering also the deleterious effect of S100A8/A9 on joint destruction in OA, targeting these alarmins during OA may be very promising.
Acute Encephalopathy Due to Water Intoxication
Authors: August G. Swanson, Oscar A. Iseri
Journal: New England Journal of Medicine (1958)

IT is generally considered that healthy persons can drink large quantities of water without ill-effect.1 This communication reports 2 cases of acute delirium and convulsions that followed the voluntary ingestion of massive volumes of water.Water intoxication usually occurs in patients who have a predisposing illness that compromises the ability of the kidneys to handle a large water load. Symptoms of delirium and convulsions induced in a healthy person by the voluntary ingestion of excess water have been recorded in the literature only once. Barahal2 reported the case of a female patient with schizophrenia who drank "gallons of water" in . . .
Abstract 1495: Tyrosine phosphorylation of galectin-3 regulated its cleavage by PSA
Authors: Vitaly Balan, Pratima Nangia-Makker, Avraham Raz
Journal: Cancer Research (2011)

Abstract Galectin-3, one of 15 animal lectins, is an intracellular and extracellular lectin which interacts with intracellular glycoproteins, cell surface molecules and extracellular matrix proteins. Recent research revealed that galectin-3 (gal-3) is involved in various biological phenomena including cell growth, adhesion, angiogenesis, apoptosis, motility and metastasis. This protein is widely expressed in various tumor cells and its expression is correlated with tumorigenesis, tumor progression and metastasis. The functions of gal-3 are dependent on its binding partners, its localization and can change as a result of post-translational modifications such as cleavage and phosphorylation. Recently we demonstrated that gal-3 can be phosphorylated by c-Abl at Tyr 79, 107 and 118; Tyr107 is the major phosphorylation site. In a recent report Saraswati et al revealed that gal-3 can be cleaved by prostate specific antigen after Tyr107. Our research confirms their data and demonstrates that phosphorylation of Tyr107 blocks this cleavage. This cleavage removes the collagen like sequence from carbohydrate binding domain of gal-3 and reduces the ability of gal-3 to create oligomers, thus blocking its ability to create lattice and promote cancer behavior of the cells. These results indicate an important role of post-translational modifications of galectin-3 in prostate 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 1495. doi:10.1158/1538-7445.AM2011-1495
Abstract 4069: FGFR2 expression and mutation are rare in papillary renal cell carcinoma.
Authors: Ilya V. Tsimafeyeu, Nigel Wynn, Marat Gordiyev, Alfia Khasanova
Journal: Cancer Research (2013)

Abstract Papillary renal cell carcinoma (pRCC) is the second most common type of renal cell carcinoma (RCC). Fibroblast growth factor receptor (FGFR) 1 signaling has been implicated to play a role in RCC (Tsimafeyeu et al. ASCO meeting 2010). We evaluated expression and mutational activation of FGFR2 as a potential target for therapy of pRCC. Formalin-fixed, paraffin-embedded specimens of removed 71 primary tumors from untreated pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 62 paraffin-embedded pRCC samples. Expression of FGFR2 was observed in 8.5% of primary pRCC (6/71). Intensity was 3+ in all cases. 2 of 71 (3%) patients had nuclear FGFR2 expression. FGFR2 S252W mutation was detected at low frequency (1/62, 1.6%) in pRCC (type I). No N549K mutation was detected in pRCC (0/43). FGFR2 expression and mutation are rare across papillary types of RCC. This study was supported by Mr. Sergey Kartashov. Citation Format: Ilya V. Tsimafeyeu, Nigel Wynn, Marat Gordiyev, Alfia Khasanova. FGFR2 expression and mutation are rare in papillary renal cell carcinoma. [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 4069. doi:10.1158/1538-7445.AM2013-4069
Abstract PD06-10: Clinical Score for Deciding a Sentinel Node Biopsy(SNB) after Neo Adjuvant Treatment(NAC) for Breast Cancer
Authors: J Cagnat, S Alran, A Savignioni, J-Y Pierga, C Belichard, Y Kirova, RJ. Salmon
Journal: Cancer Research (2010)

Abstract Rationale: Selection of the best candidates for SNB after NAC remains under discussion. A retrospective study identified predictive factors for negative axillary dissection. A score was developed to select patients at high and low risk for metastatic SNB after NAC. Patients and methods: In 776 patients receiving NAC, clinico biologic patterns were evaluated by a multivariate logistic regression model in order to to predict the negativity of axillary dissection after surgical treatment. A 4 class score was created using the three significant factors: Initial clinical node status, oestrogen receptors positivity and clinical response to treatment. This model was then prospectively applied tto 180 patients between 2006-8 Results: The probability of having a negative axillary dissection in patients with a score 0, 0-2 and over 2 was respectively 80%, 56% and less than 50%. Conclusion: We developed a simple and reproducible score to predict the likelihood of having a negative axilla after NAC and consequently to better select the good candidates for SNB after NAC Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-10.
The Cancer Information Service: The National Picture
Authors: C. D. Hallett
Journal: JNCI Journal of the National Cancer Institute (1989)

The Cancer Information Service: The National Picture Cynthia D. Hallett Cynthia D. Hallett Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 15, 2 August 1989, Pages 1130–1131, https://doi.org/10.1093/jnci/81.15.1130 Published: 02 August 1989
Prevalence of Hemochromatosis among 11,065 Presumably Healthy Blood Donors
Authors: Corwin Q. Edwards, Linda M. Griffen, David Goldgar, Charles Drummond, Mark H. Skolnick, James P. Kushner
Journal: New England Journal of Medicine (1988)

There is evidence that iron loading and organ damage can be prevented in patients with hemochromatosis if prophylactic phlebotomy is employed early in the disease--findings emphasizing the importance of early detection before clinical signs occur. This study was designed to determine the efficacy of transferrin saturation as a screening tool for hemochromatosis and to assess the frequency of homozygosity for the HLA-linked hemochromatosis gene in a healthy population. We screened 11,065 presumably healthy blood donors (5840 men and 5225 women). Donors with transferrin saturations of 62 percent or more after an overnight fast were considered potential homozygotes and were asked to undergo liver biopsy and pedigree analysis. The frequency of values for transferrin saturation of 62 or higher in men was 0.008 and in women 0.003. Thirty-eight persons with values higher than 62 were studied in detail; 35 underwent liver biopsy. Liver iron stores ranged from normal to markedly increased. Twelve siblings with an identical HLA match to a proband underwent liver biopsy, and 11 had increased liver iron stores. According to likelihood analysis of the pedigrees, 26 of the 38 probands were homozygotes, and 12 were heterozygotes. The estimated frequency of homozygosity was based on the data in men, because the threshold value of 62 for the transferrin saturation identified only half as many female homozygotes as expected. The frequency of homozygosity was 0.0045, corresponding to a gene frequency of 0.067. The value of population screening is demonstrated in these studies by the detection of homozygotes before clinical manifestations of hemochromatosis occur.