tbuckley/cabot-search huggingface dataset:
Abstract 1320: Over expression of HGF accelerates hepatitis B virus-induced liver carcinogenesis and hastens the malignancy of hepatocellular carcinoma
Authors: Qian Xie, Yanli Su, Karl Dykema, Julie Koaman, Curt Essenburg, Robert Bradley, Keiichi Iwava, Shuhji Seki, SokKean Khoo, Kyle Furge, George F. VandeWoude, Shinomiya Nariyoshi
Journal: Cancer Research (2012)

Abstract Genetically modified mouse models play important roles in improving our understanding of HGF/MET signaling in liver development, regeneration and in tumor formation. To evaluate the role of HGF/MET in HBV induced HCC, we generated 1) alb-Cre-Metflox/flox mice which lack of MET expression in the liver; 2) a mouse strain over-expressing human HGF (C3HHGF) to determine if MET is required for HCC development and how HGF accelerates HCC malignancy. We show here that overexpression of human HGF in a C3HHGF mouse model induced spontaneous hepatocellular carcinoma (HCC). Such overexpression also accelerated hepatitis B virus (HBV) surface antigen expression in the liver, which in turn selectively promoted the growth of Met-positive hepatocytes and ultimately led to hepatocellular carcinogenesis. We also demonstrate here that HCC in C3HHGF mice presented gene expression patterns highly associated with malignant human HCC. Molecularly, the HCCs of C3HHGF mice had up-regulated VEGF/HGF signal pathways that can be effectively inhibited by pathway inhibitors. We conclude that C3HHGF mouse model can serve as a good tool for studying human HCC, and we suggest that anti-angiogenic therapeutics can be applied for the treatment of HGF-driven HCC. 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 1320. doi:1538-7445.AM2012-1320
Abstract 4086: Location matters: The impact of the location of CpG sites on the specificity of methylation biomarkers for HCC
Authors: Surbhi Jain, Sitong Chen, Selena Y. Lin, Batbold Boldbaatar, Lijia Xie, Ting-Tsung Chang, Chi-Tan Hu, James P. Hamilton, Alison A. Evans, Wei Song, Stephen J. Meltzer, Timothy M. Block, Ying-Hsiu Su
Journal: Cancer Research (2012)

Abstract Hepatocellular carcinoma (HCC) is the second fastest growing cancer and one of the top 10 causes of cancer deaths in the United States. The 5-year survival rate is 14%, ranging from 26% among early stage tumors to only 2% in late stage HCC. The only available biomarker for screening, serum alpha-fetoprotein (AFP), has a low sensitivity of detection (40%-60%), so the need for a better detection method is urgent. Given the heterogeneous nature of HCC, a panel of genetic and epigenetic biomarkers would be needed to obtain high sensitivity for the early diagnosis of HCC. In the course of assembling a panel of epigenetic markers for HCC, we noticed variable HCC specificity of three extensively studied potential methylation biomarkers, APC, GSTP1, and RASSF1A. We hypothesized that the specificity of promoter methylation of the tumor suppressor genes APC, GSTP1, and RASSF1A as a biomarker for HCC could depend upon the location of the CpG sites analyzed. To test this hypothesis, we used bisulfite-PCR sequencing to compare the methylation status of the promoter region of these three genes in DNA isolated from HCC, matched adjacent non-HCC, cirrhosis, hepatitis, and normal liver. We identified HCC-specific CpG methylation sites and unique liver-specific methylation patterns in the promoter region of the APC (Jain et. al, PloSOne 2011) and GSTP1 genes and in a more HCC-specific promoter region (p &amp;lt; 0.05 by Fisher's exact test) of the RASSF1A gene. Together, these results proved our hypothesis and provided an interpretation for the variability in the literature. Using PCR-based technology, we have developed assays for a panel of genetic and epigenetic markers for liver cancer screening. These assays were first tested in tissue to determine their ability to distinguish HCC (n=120) from cirrhosis (n=35) and hepatitis (n=35). The AUROC is 0.809 for mAPC, 0.756 for mGSTP1, 0.887 for mRASSF1, and 0.733 for TP53. When combined, this panel of DNA markers had an AUROC of 0.931 and identified 90% of AFP-negative tumors. This study clearly demonstrates (1) the importance of location of CpG site methylation for HCC specificity and the way in which liver-specific DNA methylation should be considered when an epigenetic DNA marker is studied for detection of HCC and (2) the potential of a sensitive DNA test for HCC screening. An analysis of the performance of this panel of markers in peripherals (blood and urine) for HCC screening is in progress. 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 4086. doi:1538-7445.AM2012-4086
Case 51-1991
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, W.S. Beck, J.A. Ferry
Journal: New England Journal of Medicine (1991)

Presentation of Case First admission. A 66-year-old man was admitted to the hospital because of fever, sweats, and diarrhea.He was well until three months earlier, when diarrhea began and gradually worsened. Two months before entry, night sweats developed. The patient traveled to the Caribbean area, where he experienced marked anorexia and drenching night sweats; the diarrhea became more profuse and malodorous, and he occasionally observed bright-red blood dripping into the toilet after the passage of stools. Fever developed. He lost 14 kg in weight during the six weeks before entry to the hospital.Six days before admission the . . .
Immunologic Factors and Clinical Activity in Systemic Lupus Erythematosus
Authors: Peter H. Schur, John Sandson
Journal: New England Journal of Medicine (1968)

To clarify the association between certain immunologic factors and clinical activity in patients with systemic lupus erythematosus, 96 patients were studied. Those with antibodies to deoxyribonucleic acid (DNA) or heat-denatured DNA, or with serum complement levels of less than 50 C′H50 units per ml, were more likely to have renal involvement. Very low complement levels and high titers of complement-fixing antibodies to DNA were always associated with active disease, especially active renal disease, whereas the absence of these abnormalities usually indicated inactive renal disease. A 50 per cent fall in serum complement levels in 22 patients was accompanied by, or preceded the onset of, active nephritis in 19 patients. These serologic factors may thus reflect the in vivo formation of immune complexes that cause nephritis. Serial immunochemical observations may be useful in the management of patients with systemic lupus erythematosus.
P23 * MANAGEMENT AND OUTCOME OF ADULT MEDULLOBLASTOMAS: ARE WE FOLLOWING RECOMMENDED GUIDELINES?
Authors: N. Srikandarajah, R. Zakaria, A. Barborie, D. J. Husband, M. D. Jenkinson
Journal: Neuro-Oncology (2014)

INTRODUCTION: Medulloblastomas are very rare tumours in adults compared to children. Clinical pathways for medulloblastoma are well established for children. The purpose of this study was to analyse clinical outcome of adult medulloblastomas. METHOD: Single centre retrospective case review from 1995 - 2012. Clinical, radiological and neuropathological data were gathered and analysed. RESULTS: 13 patients (9 male, 4 female) were identified; median age 24 years (range: 17-64). Annual incidence in our region is 0.2 cases per million per year. Headache was the most common presenting symptom, mean duration before diagnosis was 8 weeks. Tumours were located in lateral cerebellum (n = 10) and vermis (n = 3). All patients had localized disease at presentation and underwent surgical resection and tissue biobanking followed by cranio-spinal irradiation. Three patients also received adjuvant chemotherapy. MRI spine and CSF analysis were only completed after surgery in all cases. Median follow-up was 32 months (range: 3-126). Mean overall survival (OS) was 92 months (95%CI 62-122 months) with 5 year OS of 55%. Progression free survival (PFS) was 77% with median follow-up of 32 months falling to 56% at 5 years. Three of 13 cases (23%) recurred at a mean of 38 months. All patients who received adjuvant chemotherapy remained recurrence free. CONCLUSION: Diagnosis of adult medulloblastoma is often only made after surgery. Staging MRI should occur pre-operatively to minimize artifact. In our series, surgery and craniospinal radiotherapy was the primary treatment and the role of chemotherapy could be further beneficial. There may be a role for regional management of these very rare tumours.
Abstract LB-239: The Rho GEF, GEF-H1, is regulated by and activates Rho in response to 3-D collagen matrix density in breast epithelial cells
Authors: Heck N. Jessica, Suzanne M. Ponik, Paolo P. Provenzano, Patricia J. Keely
Journal: Cancer Research (2010)

Abstract Cell interactions with the extracellular matrix (ECM) have a profound influence on carcinoma progression, invasion, and metastasis. We and others have established that breast epithelial cells sense and respond to the stiffness of their ECM environment using the small GTPase Rho, however the exact signaling mechanism has not been identified. In addition to Rho, focal adhesion kinase (FAK) has been linked to mechanosensing, and studies from our lab have revealed FAK as a key mediator of breast tumor progression. We have found that mammary specific deletion of FAK results in tumors that are neither locally invasive nor metastatic. Expression analysis from FAK−/− tumors demonstrated that a number of Rho regulatory molecules were regulated by FAK. Of particular interest, mRNA for the Rho GEF, GEF-H1, was significantly decreased in FAK−/− mammary tumors. While relatively little is known about GEF-H1, it has been implicated in the crosstalk between microtubules and the actin cytoskeleton, positioning it as a potential regulator of Rho-mediated contractility. While it is established that Rho activity is regulated by matrix stiffness, Rho regulatory molecules that modulate signaling in 3D matrices, and specifically in response to changes in matrix stiffness, have yet to be identified. Here we demonstrate that the Rho specific exchange factor, GEF-H1, is activated by and in turn regulates Rho activation as well as Rho-mediated contractility in breast epithelial cells in response to 3D matrix density. Because we have demonstrated that extracellular signal-regulated kinase (ERK) is activated in response to increased 3D collagen matrix density, and others have shown that ERK signaling modulates GEF-H1 exchange activity for RhoA, we are investigating whether ERK mediates mechanosignaling to GEF-H1. Additional studies are underway to determine the role of GEF-H1 in 3D breast cell invasion. 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 LB-239.
Identification of intraductal papillary mucinous neoplasm by esophagogastroduodenoscopy
Authors: K. Abe, A. Isono, T. Ebato, T. Yamamoto, T. Ishii, H. Kita, Y. Kuyama, F. Kondo
Journal: Endoscopy (2013)

Some reports have described identification of intraductal papillary mucinous neoplasm (IPMN) penetrating to the stomach by esophagogastroduodenoscopy (EGD) [1] [2] [3] [4]. However, it seems that detecting an IPMN from within a postoperative pancreatogastric fistula is very rare.
Inspiration of the functional localization of a US naval hospital ship on a Chinese hospital ship
Authors: Da-Wei Li, Zhi-Cheng Zhang, Wen-Ya Zhu, Tao Sun
Journal: Military Medical Research (2016)

Through the experience of being stationed on the USS Mercy hospital ship (T-AH19) and a preliminary comprehension of the personnel and material arrangements, processing and functional formats, and the multi-platform contributions of US Navy hospital ships, we briefly introduce the characteristics of US hospital ships regarding medical support, emergency rescue exercises, communications and training, international humanitarian aid, etc. We discuss the function and responsibility of Chinese hospital ships, focusing on the investigation of the construction mode and positioning in the navy.
DIVERTICULOTOMÍA ENDOSCÓPICA DE ZENKER. EXPERIENCIA INICIAL EN EL H. 12 DE OCTUBRE
Authors: AJ Del Pozo-García, S Rodríguez-Muñoz, F Sánchez-Gómez, JC Marín-Gabriel, J Díaz-Tasende, S Sáenz-López, G Castellano
Journal: Endoscopy (2011)

Introducción: El divertículo de Zenker (DZ) es un falso divertículo que se produce en un área de debilidad del músculo constrictor faríngeo inferior condicionando disfagia, tos, disfonía, broncoaspiración, cervicalgia y halitosis. Su tratamiento estándar es la diverticulectomía quirúrgica. Se han desarrollado diversas técnicas endoscópicas para su tratamiento.
Abstract 350: Inhibition of SHP2 impairs oncogenic activity of EGFR mutants in non-small cell lung cancer.
Authors: Valentina E. Schneeberger, Yuan Ren, Noreen Luetteke, Hartmut Berns, Liwei Chen, Harshani R. Lawrence, Nicholas J. Lawrence, Alex S. Lopez, Eric B. Haura, Domenico Coppola, Jie Wu
Journal: Cancer Research (2013)

Abstract Activating mutations of epidermal growth factor receptor (EGFR) are found in 5-15% of non small cell lung carcinomas (NSCLC) and are targets of NSCLC treatment. However, most patients treated with EGFR tyrosine kinase inhibitors eventually acquire drug resistance, pointing to the need of evaluating other molecules as potential targets for developing new therapy for NSCLC. The protein tyrosine phosphatase (PTP) SHP2 mediates signaling of growth factor receptors including that of EGFR. SHP2 is activated by EGFR mutants in lung adenocarcinoma. Inhibition of SHP2 with the SHP2 PTP inhibitor SPI-112Me or SHP2 knockdown suppressed proliferation of EGFR-dependent HCC827 and H1975 cells. To assess the role of Shp2 in the transgenic mouse model of EGFR mutant-driven lung cancer, we generated transgenic mice carrying a doxycycline (dox)-inducible, PTP-defective SHP2 (tetO-SHP2CSDA). Bitransgenic CCSP-rtTA/tetO-SHP2CSDA mice were crossed with tetO-EGFRL858R mice. F1 offspring of dox-induced transgenic mice were analyzed. Erk1/2 and Src were activated by EGFRL858R in bitransgenic CCSP-rtTA/tetO-EGFRL858R mice. Both of them were suppressed by SHP2CSDA in CCSP-rtTA/tetO-EGFRL858R/tetO-SHP2CSDA tritransgenic mice. Importantly, expression of SHP2CSDA significantly inhibited EGFRL858R-induced lung tumor in the tritransgenic mice. These results suggest that SHP2 is critical for lung tumorigenesis mediated by EGFR mutations. Citation Format: Valentina E. Schneeberger, Yuan Ren, Noreen Luetteke, Hartmut Berns, Liwei Chen, Harshani R. Lawrence, Nicholas J. Lawrence, Alex S. Lopez, Eric B. Haura, Domenico Coppola, Jie Wu. Inhibition of SHP2 impairs oncogenic activity of EGFR mutants in non-small cell lung cancer. [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 350. doi:10.1158/1538-7445.AM2013-350
TRATAMIENTO ENDOSCÓPICO EN PACIENTES SELECCIONADOS CON ADENOCARCINOMA SUBMUCOSO SOBRE ESÓFAGO DE BARRETT -
Authors: C Guarner-Argente, GW Falk, GG Ginsberg
Journal: Endoscopy (2011)

Introducción: El riesgo de diseminación linfática del adenocarcinoma submucoso sobre esófago de Barrett se estima entre el 7 y el 50%. Por ello, la esofaguectomía es el tratamiento de elección. En pacientes con comorbilidades, esperanza de vida corta o que rechazan la cirugía, la resección endoscópica puede ser una opción.
Abstract P1-04-05: Role of the Rb and p53 Tumor Suppressor Pathways in Mammary Tumorigenesis
Authors: RA Jones, JC Liu, J Zhe, AA Schimmer, Z Eldad
Journal: Cancer Research (2012)

Abstract The retinoblastoma (Rb) and p53 tumor suppressor pathways are frequently altered in human malignancies including breast cancer. To investigate the role of these pathways in mammary tumorigenesis, we crossed mice expressing Cre recombinase in the mammary epithelium (MMTV-Cre) with mice harboring Rb and p53 floxed alleles to generate MMTV-Cre:Rbf/f:p53f/f mutant mice. Combined somatic loss of Rb and p53 led to the formation of aggressive triple-negative tumors (ER−, PR−, HER2−) that often displayed features of an epithelial to mesenchymal transition (EMT) including sarcomatoid differentiation and high expression of the mesenchymal marker N-Cadherin. Molecular profiling revealed Rb/p53 deficient tumors shared similar gene expression profiles with mouse and human claudin-low breast cancers. Interstingly, limiting dilution transplantation analysis also suggests that Rb/p53 deficient claudin-low tumors are enriched for tumor-initiating cells (TICs). To investigate the cellular origin of claudin-low tumors, the Rbf/f and p53f/f alleles were deleted within the luminal and basal compartments of the mammary gland using a Cre-expressing adenovirus (Ad-Cre) and CD24-CD49f-based FACS analysis. The different cellular fractions were then transplanted into the cleared mammary fat pad of recipient mice which are currently being monitored for tumor development. Finally, primary cell lines isolated from Rb/p53 deficient mammary tumors were used in conjunction with high-throughput chemical and genetic screens to identify new therapeutic targets. A primary screen of 260 kinase inhibitors and 312 FDA-approved off-patent drugs has identified novel candidates and a genome wide negative selection (‘drop-out’) screen is currently in progress. Ultimately, the results of this research will provide important insight into the biology of triple-negative breast cancer and will lead to the identification of novel therapeutic targets for the treatment of patients living with this disease. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-05.
Abstract 183: Loss of Bad phosphorylation and Mcl-1 expression is necessary for rapid apoptosisinduced by combination of TGFα-PE and ZSTK474 in prostate cancer cells
Authors: Daniele Baiz, Dana Yancey, Young A. Choi, Vitaliy Baurin, Yelena Karpova, Sazzad Hassan, Waldemar Debinski, George Kulik
Journal: Cancer Research (2011)

Abstract Advanced androgen-independent prostate cancer is notoriously resistant to conventional systemic therapies, and at the moment there is no effective protocol for hormone-refractory advanced prostate cancer affected patients. One of possible mechanisms of such resistance is activation of the anti-apoptotic signaling PI3K/Akt pathway that is constitutively active in the 60% of advanced prostate cancers. However, multiple inhibitors of PI3K are just well studied and some have just gone on to clinical trials, but unfortunately they showed limited efficacy against prostate cancer alone. Our recent experiments has shown remarkable synergy in inducing rapid and massive apoptosis when PI3K inhibitor ZSTK474 is used in combination with Pseudomonas aeruginosa exotoxin A fragment fused with Transforming Growth Factor Alpha (TGFα-PE38). Time lapse video microscopy of prostate cancer C4-2 cell line has shown the substantial cell death within 4-6 hours with combined administration, compared to limited cell death in single agents-treated cells. Analysis of PARP and cleaved-caspase 3 fragment by Western blotting confirmed that cell death occurs via apoptosis. Quantitation of caspase 3 and 7 activity with luminescent AFC-DEVD substrate confirmed synergy in apoptosis activation by combination of TGFα-PE38 and ZSTK474, while single agents even in higher concentration did not induce substantial apoptosis within 6 hours time period. Analysis of the mechanisms underlying this synergy has shown that PI3K inhibitor ZSTK474 triggers Bad dephosphorylation, while TGFα-PE38 reduces expression levels of Mcl-1. A slight increase of Bim protein was detected and related with ZSTK474 administration. No major variations were detected in the expression levels of pro- and anti-apoptotic proteins Bax, Bcl-2 and Bcl-XL. To address the role of Bad phosphorylation and Mcl-1 expression in apoptosis induction by PI3K inhibitor ZSTK474 and TGFα-PE38, we examined apoptosis in C4-2 cells that express phosphorylation-deficient mutant Bad (BAD2SA). Results indicated that the expression of BAD2SA sensitized C4-2 cells to apoptosis induced by TGFα-PE38. Experiments that address the role of Mcl-1 loss in apoptosis induced by TGFα-PE38 are ongoing. 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 183. doi:10.1158/1538-7445.AM2011-183
US clinical research under threat
Authors: J. H. Tanne
Journal: BMJ (1997)

Clinical research in the United States is facing a crisis largely due to the growth in managed care, the Institute of Medicine and the American Medical Association warned last week.

“The real problem is that American society is trying to control healthcare costs. Managed care organisations are the mechanism through which this is expressed,” said Dr Kenneth Shine, president of the Institute of Medicine, part of the National Academy of Sciences. Academic medical centres, whose costs are 15-30% higher because of research and education, are forced to compete with community hospitals.

The Institute of Medicine organised a two day meeting in Washington, DC, to highlight these concerns; it coincided with a special issue of JAMA . The biggest single problem, Dr Shine said, is that clinical researchers are losing time to do research as their hospitals press them to see more patients. Basic science researchers usually hold a PhD qualification and so cannot be redirected to the care …