tbuckley/cabot-search huggingface dataset:
Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation
Authors: Jeffrey A. Knauf, Xiaolan Ma, Eric P. Smith, Lei Zhang, Norisato Mitsutake, Xiao-Hui Liao, Samuel Refetoff, Yuri E. Nikiforov, James A. Fagin
Journal: Cancer Research (2005)

Abstract The BRAFT1799A mutation is the most common genetic alteration in papillary thyroid carcinomas (PTC). It is also found in a subset of papillary microcarcinomas, consistent with a role in tumor initiation. PTCs with BRAFT1799A are often invasive and present at a more advanced stage. BRAFT1799A is found with high prevalence in tall-cell variant PTCs and in poorly differentiated and undifferentiated carcinomas arising from PTCs. To explore the role of BRAFV600E in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BRAFV600E lines (Tg-BRAF2 and Tg-BRAF3) were propagated for detailed analysis. Tg-BRAF2 and Tg-BRAF3 mice had increased thyroid-stimulating hormone levels (&amp;gt;7- and ∼2-fold, respectively). This likely resulted from decreased expression of thyroid peroxidase, sodium iodine symporter, and thyroglobulin. All lines seemed to successfully compensate for thyroid dysfunction, as serum thyroxine/triiodothyronine and somatic growth were normal. Thyroid glands of transgenic mice were markedly enlarged by 5 weeks of age. In Tg-BRAF2 mice, PTCs were present at 12 and 22 weeks in 14 of 15 and 13 of 14 animals, respectively, with 83% exhibiting tall-cell features, 83% areas of invasion, and 48% foci of poorly differentiated carcinoma. Tg-BRAF3 mice also developed PTCs, albeit with lower prevalence (3 of 12 and 4 of 9 at 12 and 22 weeks, respectively). Tg-BRAF2 mice had a 30% decrease in survival at 5 months. In summary, thyroid-specific expression of BRAFV600E induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas. This closely recapitulates the phenotype of BRAF-positive PTCs in humans and supports a key role for this oncogene in its pathogenesis.
Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib
Authors: Jurjan Aman, Jan van Bezu, Amin Damanafshan, Stephan Huveneers, Etto C. Eringa, Steven M. Vogel, A.B. Johan Groeneveld, Anton Vonk Noordegraaf, Victor W.M. van Hinsbergh, Geerten P. van Nieuw Amerongen
Journal: Circulation (2012)

Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case report, we described fast resolution of pulmonary edema on treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation.We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro- and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. Small interfering RNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-related gene kinase (Arg/Abl2), a previously unknown mediator of endothelial barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extracellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against vascular endothelial growth factor-induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis, imatinib treatment (6 hours and 18 hours after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24 hours after induction of sepsis).Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema and indicate Arg as novel target for edema treatment.
Response to ‘Evidence in Support of the Validity of the TNF Brake Hypothesis’ by Maksymowych
Authors: Xenofon Baraliakos, Jürgen Braun
Journal: Annals of the Rheumatic Diseases (2013)

Background: The efficacy and toxicity of adjuvant chemo-immunotherapy using dendritic cells and activated killer cells are not clear in post-surgical primary lung cancer patients. Patients and Methods: Pathologically diagnosed N2 lung cancer patients were selected for post-surgical adjuvant chemo-immunotherapy. The activated killer cells and dendritic cells (AKT-DC) obtained from tissue cultures of tumor-draining lymph nodes (TDLN) or from TDLN co-cultured with peripheral blood lymphocytes (TDLN-Pb) were used for the adoptive transfer of immunotherapy. The patients received 4 courses of chemotherapy along with immunotherapy every 2 months for 2 years. Results: There were 31 N2 patients eligible for the study. Three cases were excluded because of refusal by the patients after 1-2 courses of immunotherapy. For the 28 cases treated, a total of 313 courses of immunotherapy were administered. The main toxicities were fever (78.0%), chill (83.4%), fatigue (23.0%) and nausea (17.0%) on the day of cell transfer. The 2- and 5-year survival rates were 88.9% (95.9-81.9; 95% confidence interval, C.I.) and 52.9% (76.4-29.4; C.I.). Conclusion: Adoptive transfer of activated killer cells and dendritic cells from the tumor-draining lymph nodes of primary lung cancer patients is feasible and safe, and a large-scale multi-institutional study is necessary for evaluation of the efficacy of this treatment.
<i>NHERF1</i>Mutations and Responsiveness of Renal Parathyroid Hormone
Authors: Zoubida Karim, Bénédicte Gérard, Naziha Bakouh, Rohia Alili, Christine Leroy, Laurent Beck, Caroline Silve, Gabrielle Planelles, Pablo Urena-Torres, Bernard Grandchamp, Gérard Friedlander, Dominique Prié
Journal: New England Journal of Medicine (2008)

Impaired renal phosphate reabsorption, as measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), increases the risks of nephrolithiasis and bone demineralization. Data from animal models suggest that sodium-hydrogen exchanger regulatory factor 1 (NHERF1) controls renal phosphate transport. We sequenced the NHERF1 gene in 158 patients, 94 of whom had either nephrolithiasis or bone demineralization. We identified three distinct mutations in seven patients with a low TmP/GFR value. No patients with normal TmP/GFR values had mutations. The mutants expressed in cultured renal cells increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport. These NHERF1 mutations suggest a previously unrecognized cause of renal phosphate loss in humans.
Application of antimicrobial photodynamic therapy in periodontal and peri‐implant diseases
Authors: Aristeo A. Takasaki, Akira Aoki, Koji Mizutani, Frank Schwarz, Anton Sculean, Chen‐Ying Wang, Geena Koshy, George Romanos, Isao Ishikawa, Yuichi Izumi
Journal: Periodontology 2000 (2009)
Plethysmographic measurements of lung volume and airway resistance
Authors: J. Stocks, S. Godfrey, C. Beardsmore, E. Bar-Yishay, R. Castile
Journal: European Respiratory Journal (2001)

Functional residual capacity (FRC) is the only static lung volume that can be measured routinely in infants. It is important for interpreting volume-dependent pulmonary mechanics such as airway resistance or forced expiratory flows, and for defining normal lung growth. Despite requiring complex equipment, the plethysmographic method for measuring FRC is very simple to apply and, unlike the gas dilution techniques, enables repeat measures of lung volume to be obtained within a few minutes. This method has the further advantage that with suitable adaptations to the equipment, simultaneous measurements of airway resistance can also be obtained. The aim of this paper is to provide recommendations pertaining to equipment requirements, study procedures and reporting of data for plethysmographic measurements in infants. Implementation of these recommendations should help to ensure that such measurements are as accurate as possible and that meaningful comparisons can be made between data collected in different centres or with different equipment. These guidelines cover numerous aspects including terminology and definitions, equipment, data acquisition and analysis and reporting of results and also highlight areas where further research is needed before consensus can be reached.
People make mistakes: what then?
Authors: A. Seymour
Journal: BMJ (2001)

I was eating my supper when the ward servant knocked on the door (the wires of the intercom had been nibbled by rats, and it was not working): “Nurse say, ‘Doctor please come quick.’” So I came and found a distraught nursing aide standing by a diabetic patient who had just come out of a ketoacidotic coma. “Doctor I …
Imaging of the common bile duct in patients undergoing laparoscopic cholecystectomy.
Authors: P J Hainsworth, M Rhodes, R H Gompertz, C P Armstrong, T W Lennard
Journal: Gut (1994)

Options for managing the common bile duct during laparoscopic cholecystectomy include routine peroperative cholangiography and selected preoperative endoscopic retrograde cholangiopancreatography (ERCP). The use of these methods was reviewed in 350 patients with symptomatic gall stones referred for laparoscopic cholecystectomy. Unit A (n = 114) performed routine cystic duct cholangiography but undertook preoperative ERCP in patients at very high risk of duct stones only; unit B (n = 236) performed selected preoperative ERCP on the basis of known risk factors for duct stones. The detection rate for common bile duct stones was similar for units A and B (16% v 20%). In unit A, five of seven patients who had preoperative ERCP had duct stones. Operative cholangiography was technically successful in 90% of patients and duct stones were confidently identified in 13, one of whom went on to immediate open duct exploration. Postoperative ERCP identified duct stones in only four patients, indicating spontaneous passage in eight. In unit B, preoperative ERCP was undertaken in 76 of 236 (32%) patients and duct stones were identified in 47 (20%). Duct clearance was successful in 42 (18%) but failed in five (2%), necessitating elective open duct exploration. Both protocols for imaging the common bile duct worked well and yielded satisfactory short term results.
Proteomics of gliomas: Initial biomarker discovery and evolution of technology
Authors: J. Kalinina, J. Peng, J. C. Ritchie, E. G. Van Meir
Journal: Neuro-Oncology (2011)

Gliomas are a group of aggressive brain tumors that diffusely infiltrate adjacent brain tissues, rendering them largely incurable, even with multiple treatment modalities and agents. Mostly asymptomatic at early stages, they present in several subtypes with astrocytic or oligodendrocytic features and invariably progress to malignant forms. Gliomas are difficult to classify precisely because of interobserver variability during histopathologic grading. Identifying biological signatures of each glioma subtype through protein biomarker profiling of tumor or tumor-proximal fluids is therefore of high priority. Such profiling not only may provide clues regarding tumor classification but may identify clinical biomarkers and pathologic targets for the development of personalized treatments. In the past decade, differential proteomic profiling techniques have utilized tumor, cerebrospinal fluid, and plasma from glioma patients to identify the first candidate diagnostic, prognostic, predictive, and therapeutic response markers, highlighting the potential for glioma biomarker discovery. The number of markers identified, however, has been limited, their reproducibility between studies is unclear, and none have been validated for clinical use. Recent technological advancements in methodologies for high-throughput profiling, which provide easy access, rapid screening, low sample consumption, and accurate protein identification, are anticipated to accelerate brain tumor biomarker discovery. Reliable tools for biomarker verification forecast translation of the biomarkers into clinical diagnostics in the foreseeable future. Herein we update the reader on the recent trends and directions in glioma proteomics, including key findings and established and emerging technologies for analysis, together with challenges we are still facing in identifying and verifying potential glioma biomarkers.
Patterns-of-failure analysis of patients with high pretreatment prostate-specific antigen levels treated by radiation therapy: the need for improved systemic and locoregional treatment.
Authors: G E Hanks, A L Hanlon, G Hudes, W R Lee, W Suasin, T E Schultheiss
Journal: Journal of Clinical Oncology (1996)

PURPOSE The patterns of failure (local and/or regional v metastatic) have been determined for patients with prostate cancer and pretreatment prostate-specific antigen (PSA) levels &gt; or = 20 ng/mL treated with radiation alone with the purpose to design appropriate multimodal treatments. MATERIALS AND METHODS One hundred twenty patients with pretreatment PSA levels &gt; or = 20 ng/mL were treated with external-beam radiation alone between February 1988 and October 1993. They were arbitrarily divided by PSA levels, 20 to 29.9 ng/mL, 30 to 49.9 ng/mL, and &gt; or = 50 ng/mL, and analyzed in terms of freedom from any failure (no evidence of biochemical disease [bNED], and PSA level &lt; 1.5 ngm/mL and not increasing), as well as freedom from imaging evidence of distant metastasis (fdm). RESULTS There was no significant difference in short-term outcome by pretreatment PSA level, and thus all patients were pooled for analysis. At 4 years, 81% were fdm and 28% were free of any failure. This suggests that approximately 50% have recurred with local and/or regional disease or undetectable metastatic disease. Multivariate analysis indicated that low palpation stage and higher center of prostate dose were associated with better bNED survival. Multivariate analysis indicated that increasing stage and younger age are significantly associated with increasing distant metastasis. CONCLUSION Patients with pretreatment PSA levels &gt; or = 20 ng/mL are not optimally treated by irradiation alone. The pattern of failure suggests improvement may come from systemic treatment of metastatic disease and high-dose radiation to improve locoregional disease. To evaluate this, we have begun a multimodal trial of chemohormonal therapy followed by extended-field irradiation.
Vascular endothelial growth factor and endometriotic angiogenesis
Authors: J. McLaren
Journal: Human Reproduction Update (2000)

Peritoneal endometriosis is a significant debilitating gynaecological problem of widespread prevalence. It is now generally accepted that the pathogenesis of peritoneal endometriosis involves the implantation of exfoliated endometrium. Essential for its survival is the generation and maintenance of an extensive blood supply both within and surrounding the ectopic tissue. The vascular endothelial growth factor (VEGF) family of angiogenic molecules is involved in both physiological angiogenesis, and a number of pathological conditions that are characterized by excessive angiogenesis. Increasing evidence suggests that the VEGF family may also be involved with both the aetiology and maintenance of peritoneal endometriosis. Sources of this factor include the eutopic endometrium, ectopic endometriotic tissue and peritoneal fluid macrophages. Important to its aetiology is the correct peritoneal environment in which the exfoliated endometrium is seeded and implants. Established ectopic tissue is then dependent on the peritoneal environment for its survival, an environment that supports angiogenesis. Our increasing knowledge of the involvement of the VEGF family in endometriotic angiogenesis raises the possibility of novel approaches to its medical management, with particular focus on the anti-angiogenic control of the action of VEGF.
Intense Dose-Dense Sequential Chemotherapy With Epirubicin, Paclitaxel, and Cyclophosphamide Compared With Conventionally Scheduled Chemotherapy in High-Risk Primary Breast Cancer: Mature Results of an AGO Phase III Study
Authors: Volker Moebus, Christian Jackisch, Hans-Joachim Lueck, Andreas du Bois, Christoph Thomssen, Christian Kurbacher, Walther Kuhn, Ulrike Nitz, Andreas Schneeweiss, Jens Huober, Nadia Harbeck, Gunter von Minckwitz, Ingo B. Runnebaum, Axel Hinke, Rolf Kreienberg, Gottfried E. Konecny, Michael Untch
Journal: Journal of Clinical Oncology (2010)

Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy. We compared intense dose-dense (IDD) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer.In this randomized, phase III trial, a total of 1,284 eligible patients with four or more involved axillary lymph nodes were randomly assigned to receive IDD sequential epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks. The primary end point was event-free survival (EFS).At a median follow-up of 62 months, 5-year event-free survival rates were 62% in the conventional arm and 70% in the IDD-ETC arm, representing a 28% reduction of the relative risk of relapse (P < .001). This benefit was independent of menopausal, hormone receptor, or human epidermal growth factor receptor 2 status. The 5-year overall survival rates were 77% versus 82%, representing a 24% reduction of the relative risk of death (P = .0285). IDD therapy was associated with significantly more nonhematologic and hematologic toxicities, but no treatment-related death occurred. Four occurrences of acute myeloid leukemia or myelodysplastic syndrome (MDS) were observed in the IDD-ETC arm. No severe congestive heart failure was reported.IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes.
Changes in RNA polymerase II progression influence somatic hypermutation of Ig-related genes by AID
Authors: Prashant Kodgire, Priyanka Mukkawar, Sarayu Ratnam, Terence E. Martin, Ursula Storb
Journal: The Journal of Experimental Medicine (2013)

Somatic hypermutation (SHM) of Ig genes is initiated by the activation-induced cytidine deaminase (AID), and requires target gene transcription. We previously proposed that AID may associate with the RNA polymerase II (Pol). Here, to determine aspects of the transcription process required for SHM, we knocked-in a transcription terminator into an Ig gene variable region in DT40 chicken B cell line. We found that the human β-globin terminator was an efficient inhibitor of downstream transcription in these cells. The terminator reduced mutations downstream of the poly(A) signal, suggesting that the process of transcription is essential for efficient SHM and that AID has better access to its target when Pol is in the elongating rather than terminating mode. Mutations upstream of the poly(A) site were almost doubled in the active terminator clones compared with an inactivated terminator, and this region showed more single-stranded DNA, indicating that Pol pausing assists SHM. Moreover, the nontranscribed DNA strand was the preferred SHM target upstream of the active terminator. Pol pausing during poly(A) site recognition may facilitate persistence of negative supercoils, exposing the coding single strand and possibly allowing the nascent RNA intermittent reannealing with the template strand, for prolonged access of AID.
Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis
Authors: Daniel J. Hicklin, Lee M. Ellis
Journal: Journal of Clinical Oncology (2004)

New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.
Are re-admissions with acute exacerbation of chronic obstructive pulmonary disease coded correctly?
Authors: Maryam Ahmed, Barbara Rickard, Carol Lynch, Gill Owen, Steve Bradbury, Karen Leech, Martin Allen
Journal: European Respiratory Journal (2014)

Background:  Re-admissions are common and challenging for hospitals across the UK. They not only affect patients but also have financial implications for trusts. A hospital re-admission with the same clinical condition within 30 days of discharge incurs no payment. Acute exacerbation of chronic obstructive pulmonary disease (COPD) is well recognised as a cause of recurrent admissions. We have reviewed the re-admissions to our trust in a cohort of patients with COPD.   Methods:  Retrospective review of consecutive patients coded as re-admissions within 30 days with acute COPD exacerbation between September 2012 and April 2013. Electronic patient records were used to review both the index (first) admission and re-admission episodes.   Results:  A total of 915 patients were admitted with COPD during the 8 months. Of these, 135 were coded as re-admissions. On review of discharge diagnoses, 77 patients were coded correctly on the index admission and 115 on the re-admission episode. A total of 78 patients were incorrectly coded, 58 on the index admission and 20 on re-admission. 73 (54%) of the 135 coded re-admissions were identified as definite re-admissions. The remaining 62 (46%) were not re-admitted within 30 days of the first admission and thus incorrectly coded.   Conclusion:   Almost 50% of patients coded as re-admissions with acute exacerbation of COPD were inaccurate. Clinical coding needs to improve in order to minimise and avoid financial penalties.
Utility of Adding Primovist Magnetic Resonance Imaging to Analysis of Hepatocellular Carcinoma by Liver Dynamic Computed Tomography
Authors: Young-Joo Jin, So-Yun Nah, Jin-Woo Lee, Jung-Il Lee, Seok Jeong, Don Haeng Lee, Young Soo Kim, Soon Gu Cho, Yong Sun Jeon
Journal: Clinical Gastroenterology and Hepatology (2012)