tbuckley/cabot-search huggingface dataset:
Abstract 2038: Unraveling the mechanism of action: drugs that activate the tumor suppressor 2A .
Authors: Matthew D. Dun, Amanda M. Smith, Richard G. S. Kahl, Nathan D. Smith, Anchit Khanna, Anthony S. Don, Hanish F. Toop, Jonathan C. Morris, Nicole M. Verrills
Journal: Cancer Research (2013)

Abstract The tumor suppressor 2A (PP2A) is a multi-enzyme complex that targets a variety of oncogenic signaling cascades such as Raf, MEK and AKT. Numerous reports have now emerged indicating that the inhibition of PP2A leads to the development of tumors including breast, gastric and lung and a range of hematological malignancies such as chronic and acute myeloid leukemia (CML and AML, respectively). We and others have shown that inhibition of PP2A is crucial for the oncogenic effects of leukemia associated receptor tyrosine kinases such as BCR/Abl, c-KIT and FLT3. Importantly when PP2A is reactivated using pharmacological agents (FTY720 and AAL(S)), growth and survival of these cells is inhibited. This approach targets molecules downstream of these oncogenic kinases and thus PP2A reactivation is designed to avoid resistance associated with kinase inhibitor therapy. As the mechanism of action of these PP2A activators is unknown, it is essential that we now determine the molecular targets of these compounds to generate more effective drugs. Using a chemical proteomics approach incorporating click chemistry linking the drugs to beads, unbiased pull down assays were performed in myeloid leukaemia cells and protein isolates were identified by mass spectrometry. Using this approach we have identified a novel cellular target, which is known to be overexpressed in a range of cancers, including leukemias. We have also shown that this protein associates with PP2A complexes in these cells, and thus may act as an endogenous inhibitor of PP2A activity. We have also performed phospho-proteomics and co-immunoprecipitation studies to identify protein changes in myeloid leukemia cells in response to PP2A activators. In addition to identifying known PP2A targets, such as Akt and ERK, we have also identified a number of novel protein changes, including altered expression of the SET oncoprotein. SET is a known inhibitor of PP2A, suggesting that FTY720 may act via inhibition of SET. Other PP2A regulatory proteins such as CIP2A, PME-1 and PP2A-B56alpha are also affected by FTY720/AAL(S) treatment. Our research findings are thus providing the vital clues necessary for determining the mechanism of action of clinically relevant PP2A activators, thereby moving us towards the provision of novel anti-cancer treatment regimes. Citation Format: Matthew D. Dun, Amanda M. Smith, Richard G. S. Kahl, Nathan D. Smith, Anchit Khanna, Anthony S. Don, Hanish F. Toop, Jonathan C. Morris, Nicole M. Verrills. Unraveling the mechanism of action: drugs that activate the tumor suppressor 2A . [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 2038. doi:10.1158/1538-7445.AM2013-2038
Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice
Authors: Ting Hu Qiu, Gadisetti V. R. Chandramouli, Kent W. Hunter, Nawal W. Alkharouf, Jeffrey E. Green, Edison T. Liu
Journal: Cancer Research (2004)

Abstract FVB/N-Tg (MMTV-PyMT)634Mul-transgenic mice develop multifocal mammary tumors with a high incidence of pulmonary metastasis. We have demonstrated previously that mammary tumors derived from transgene-positive F1 progeny in particular inbred strains display altered latency, tumor growth rates, and metastatic rates when compared with the FVB/NJ homozygous parent. To identify genes with expression that might be critical in modifying the biological behavior of MMTV-PyMT tumors, we performed a detailed comparative analysis of expression profiles from mammary tumors arising in the parental FVB/NJ background and F1 progeny from crosses with I/LnJ, LP/J, MOLF/Ei, and NZB/B1NJ mice. Compared with normal mammary glands, gene expression profiles of tumors from all five strains exhibited up-regulation of genes involved in cell growth (e.g., Cks1 and CDC25C) and down-regulation of cell adhesion molecules, with many genes associated previously with human breast cancer such as STAT2, CD24 antigen, gelsolin, and lipocalin2. To identify genes with significant variation in expression between the five different genotypes, significance analysis of microarrays (SAM) and one-way ANOVA were used. Three definable groupings of tumors were identified: (a) tumors derived in the LP/J F1 and MOLF/Ei F1 strains in which tumor growth and dissemination are suppressed and latency prolonged; (b) the most aggressive tumors from the FVB/NJ parental strain and I/LnJ F1 genomic backgrounds; and (c) an intermediate virulence phenotype with tumors from NZB/B1NJ–F1 crosses. These array based assessments correlated well with a composite phenotype ranking using a “virulence” index. The gene expression signature that is associated with a high metastatic rate in the mouse contains the same 17 genes described recently as the signature gene set predictive of metastasis in human tumors (1) with 16 of the 17 genes exhibiting the same directional change in expression associated with human metastases. These results demonstrate that the genetic analysis of mouse models of tumorigenesis may be highly relevant to human cancer and that the metastatic phenotype of a tumor may be affected by the germline genetic configuration of the host.
Maggot Therapy for Treating Diabetic Foot Ulcers Unresponsive to Conventional Therapy
Authors: Ronald A. Sherman
Journal: Diabetes Care (2003)

OBJECTIVE—To assess the efficacy of maggot therapy for treating foot and leg ulcers in diabetic patients failing conventional therapy. RESEARCH DESIGN AND METHODS—Retrospective comparison of changes in necrotic and total surface area of chronic wounds treated with either maggot therapy or standard (control) surgical or nonsurgical therapy. RESULTS—In this cohort of 18 patients with 20 nonhealing ulcers, six wounds were treated with conventional therapy, six with maggot therapy, and eight with conventional therapy first, then maggot therapy. Repeated measures ANOVA indicated no significant change in necrotic tissue, except when factoring for treatment (F [1.7, 34] = 5.27, P = 0.013). During the first 14 days of conventional therapy, there was no significant debridement of necrotic tissue; during the same period with maggot therapy, necrotic tissue decreased by an average of 4.1 cm2 (P = 0.02). After 5 weeks of therapy, conventionally treated wounds were still covered with necrotic tissue over 33% of their surface, whereas after only 4 weeks of therapy maggot-treated wounds were completely debrided (P = 0.001). Maggot therapy was also associated with hastened growth of granulation tissue and greater wound healing rates. CONCLUSIONS—Maggot therapy was more effective and efficient in debriding nonhealing foot and leg ulcers in male diabetic veterans than was continued conventional care.
Role of MRE11 in Cell Proliferation, Tumor Invasion, and DNA Repair in Breast Cancer
Authors: Shyng-Shiou F. Yuan, Ming-Feng Hou, Ya-Ching Hsieh, Chien-Yiu Huang, Yi-Chen Lee, Yun-Ju Chen, Steven Lo
Journal: JNCI Journal of the National Cancer Institute (2012)

Previous studies have shown that altered forms of MRE11, a protein known to play a vital role in DNA double-strand break repair, DNA replication, and telomere maintenance are associated with cancer outcomes. We investigated the role of MRE11 in breast cancer in both clinical and in vitro settings. We examined MRE11 expression in tumor tissues from invasive ductal carcinoma breast cancer patients (n = 254) by immunohistochemistry, and associations with clinicopathological characteristics and overall survival were assessed using Cox proportional hazards regression models and Kaplan–Meier survival curves. Effect of MRE11 overexpression and knockdown on cell proliferation, invasion, and radioresistance was assessed in vitro using breast cancer cell lines (MCF-7 and MDA-MB-231). We also investigated the mechanisms involved. Effect of MRE11 overexpression on tumor growth was assessed in an orthotopic xenograft model (n = 8 mice per group). All statistical tests were two-sided. Of the 254 tissue samples, 69.3% and 30.7% showed high and low MRE11 expression, respectively. High MRE11 expression was statistically significantly associated with malignant cancer behavior compared with low MRE11 expression (eg, stages III and IV vs stage I, P = .004; poor overall survival, P = .005). MRE11 overexpression in breast cancer cell lines promoted cell proliferation through STAT3, cell cycle entry, invasion and migration, and radioresistance via enhanced DNA repair activity and also inhibited apoptosis; knockdown of MRE11 had the opposite effect. In xenograft tumor–bearing mice (n = 8 per group), increased tumor growth was observed in the MRE11-overexpressing group compared with the control group (tumor volume at week 8, control vs MRE11-overexpressing tumor originating from MCF-7 cells, mean = 280.4mm3, 95% confidence interval [CI] = 62.4 to 498.4mm3 vs mean = 631.0mm3, 95% CI = 296.9 to 965.0mm3, P = .043). High MRE11 expression was associated with a more malignant behavior in breast cancer. MRE11 may be a novel oncoprotein and may therefore serve as a new therapeutic intervention against breast cancer.
Can trial quality be reliably assessed from published reports of cancer trials: evaluation of risk of bias assessments in systematic reviews
Authors: C. L. Vale, J. F. Tierney, S. Burdett
Journal: BMJ (2013)

<b>Objective</b> To evaluate the reliability of risk of bias assessments based on published trial reports, for determining trial inclusion in meta-analyses. <b>Design</b> Reliability evaluation of risk of bias assessments. <b>Data sources </b>13 published individual participant data (IPD) meta-analyses in cancer were used to source 95 randomised controlled trials. <b>Review methods </b>Risk of bias was assessed using the Cochrane risk of bias tool (RevMan5.1) and accompanying guidance. Assessments were made for individual risk of bias domains and overall for each trial, using information from either trial reports alone or trial reports with additional information collected for IPD meta-analyses. Percentage agreements were calculated for individual domains and overall (&lt;66%=low, ≥66%=fair, ≥90%=good). The two approaches were considered similarly reliable only when agreement was good. <b>Results</b> Percentage agreement between the two methods for sequence generation and incomplete outcome data was fair (69.5% (95% confidence interval 60.2% to 78.7%) and 80.0% (72.0% to 88.0%), respectively). However, percentage agreement was low for allocation concealment, selective outcome reporting, and overall risk of bias (48.4% (38.4% to 58.5%), 42.1% (32.2% to 52.0%), and 54.7% (44.7% to 64.7%), respectively). Supplementary information reduced the proportion of unclear assessments for all individual domains, consequently increasing the number of trials assessed as low risk of bias (and therefore available for inclusion in meta-analyses) from 23 (23%) based on publications alone to 66 (66%) based on publications with additional information. <b>Conclusions</b> Using cancer trial publications alone to assess risk of bias could be unreliable; thus, reviewers should be cautious about using them as a basis for trial inclusion, particularly for those trials assessed as unclear risk. Supplementary information from trialists should be sought to enable appropriate assessments and potentially reduce or overcome some risks of bias. Furthermore, guidance should ensure clarity on what constitutes risk of bias, particularly for the more subjective domains.
Phase I Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors
Authors: Charles Erlichman, Manuel Hidalgo, Joseph P. Boni, Patricia Martins, Susan E. Quinn, Charles Zacharchuk, Peter Amorusi, Alex A. Adjei, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2006)

Purpose The maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors. Patients and Methods Planned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days 1 and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort. Results Thirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean ± standard deviation terminal half-life was 21.7 ± 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non–small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively. Conclusion The MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.
ANTIHAPTEN ANTIBODY SPECIFICITY AND L CHAIN TYPE
Authors: Victor Nussenzweig, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1967)

Two types of light polypeptide chain (kappa and lambda) are present in guinea pig immunoglobulins. The ratios of K/L molecules in anti-hapten antibodies differ sometimes markedly from that found in normal serum. Anti-DNP antibodies and anti-pipsyl antibodies have, respectively, a higher and a lower than normal K/L ratio. The possibility that the L chain type affects the range of configurations which the antibody-combining site may assume was investigated. Fractional precipitation of anti-DNP antibodies from serum of guinea pigs immunized with DNP(44)-BSA was performed using limiting amounts of antigen. Antibody fractions were purified from each precipitate, their affinities for epsilon-DNP-L-lysine measured by fluorescence quenching (K(0)) and the K/L ratio estimated by precipitation with specific antisera. Increasing concentrations of L molecules were found in fractions with decreasing K(0). In other experiments, fractional precipitation and purification of antibodies which cross-react with DNP was performed in serum of animals immunized with pipsyl-BGG. The K/L ratio in antibodies isolated from these fractions was much higher than in fractions which do not cross-react with DNP. These results show that K molecules are better adapted to react with the DNP hapten than L molecules. The K/L ratio in anti-DNP antibody was shown to increase in the course of immunization, at the same time that the K(0) is increasing. This rise in K(0) is markedly delayed when larger doses of antigen are employed.
The Architecture of Long-Range Haplotypes Shared within and across Populations
Authors: A. Gusev, P. F. Palamara, G. Aponte, Z. Zhuang, A. Darvasi, P. Gregersen, I. Pe'er
Journal: Molecular Biology and Evolution (2011)

Homologous long segments along the genomes of close or remote relatives that are identical by descent (IBD) from a common ancestor provide clues for recent events in human genetics. We set out to extensively map such IBD segments in large cohorts and investigate their distribution within and across different populations. We report analysis of several data sets, demonstrating that IBD is more common than expected by naïve models of population genetics. We show that the frequency of IBD pairs is population dependent and can be used to cluster individuals into populations, detect a homogeneous subpopulation within a larger cohort, and infer bottleneck events in such a subpopulation. Specifically, we show that Ashkenazi Jewish individuals are all connected through transitive remote family ties evident by sharing of 50 cM IBD to a publicly available data set of less than 400 individuals. We further expose regions where long-range haplotypes are shared significantly more often than elsewhere in the genome, observed across multiple populations, and enriched for common long structural variation. These are inconsistent with recent relatedness and suggest ancient common ancestry, with limited recombination between haplotypes.
Computed tomography colonography (virtual colonoscopy): a new method for colorectal screening
Authors: C D JOHNSON, D A AHLQUIST
Journal: Gut (1999)

Screening for colorectal polyps and neoplasms has been accepted and instituted in the United States. As most colorectal neoplasms arise from pre-existing polyps, detection and removal of precursor adenomas result in a decrease in the incidence of and mortality from colorectal cancer.1-9 Two American expert panels have recently reviewed the scientific basis of various colorectal screening tests and recommended their adoption.10 11 Furthermore, the United States Congress has recently approved national Medicare coverage for colorectal screening. A broad range of screening choices are available for patients and physicians to choose from. Depending upon the patient’s risk factors, screening choices include faecal occult blood testing, flexible sigmoidoscopy, barium enema, and colonoscopy. Unfortunately, none of the currently available colorectal screening tests is optimal in terms of examination performance, safety, or patient acceptance. Physicians and scientists interested in colorectal cancer screening continue to look for novel methods to detect adenomas and early cancers.

In 1994 using volumetric computed tomography (CT) data produced by a spiral CT scanner, CT colonography (CTC) was first introduced.12 The three dimensional images displayed in a cine loop (simulating the endoluminal views seen at colonoscopy) excited many investigators in the field of gastrointestinal imaging. Today, several academic centres in the United States are actively investigating this new technique. The purpose of this article is to review the current state of knowledge in this field, to compare CTC with other accepted colorectal screening tests, and to identify future areas of study and development.

### TECHNIQUE

Today CTC refers to an examination performed on a spiral CT scanner with acquisition of volumetric data of the entire colon. Combining these data with advanced imaging software, the colon is examined at an off-line workstation using the combination of two dimensional and three dimensional images (fig 1).



Figure 1 
Colonoscopic, endoluminal three dimensional view, …
Reactive arthritis and ruptured Achilles tendon
Authors: L STAFFORD, J BERTOUCH
Journal: Annals of the Rheumatic Diseases (1998)

It is widely accepted that reactive arthritis is associated with enthesitis. We recently saw a patient with chronic Achilles tendonitis who suffered a rupture of this tendon at the tendocalcaneal insertion.

A 22 year old male locksmith presented in December 1994 with bilateral metatarsalgia and right fourth toe dactylitis. Naproxyn was introduced with partial resolution of symptoms. In April 1995 he developed synovitis in the left knee, both ankles, and enthesitis in the right Achilles tendon, right posterior tibialis tendon, and bilateral plantar fascitis. There was no history of rash, inflammatory eye disease, back pain, gastroenteritis or genitourinary symptoms. Investigations revealed an erythrocyte sedimentation rate (ESR) of 25 mm 1st h, HLA B27 positive, increased serum IgM antibodies to Yersinia enterocolitica 05 (optical density 0.581) …
Normative values of dynamic knee valgus during single leg squat in basketball and volleyball athletes
Authors: L D Mendonça, B A J Murta, M N F Leite, N F N Bittencourt, V Castro, G G P Gonçalves, A A Silva, S T Fonseca
Journal: British Journal of Sports Medicine (2011)

Background Volleyball and basketball are among the sports with a higher incidence of knee injuries. The inability to maintain a proper alignment of the lower limbs during functional activities could create a knee valgus which predisposes to injury. Thus, the quantification of knee valgus is necessary to guide prevention and clinical interventions. Objective To establish normative values for dynamic knee valgus during the single leg squat (SLS) in volleyball and basketball athletes. Design Observational cross-sectional. Setting Minas Tênis Club, Brazil, youth sports. Participants 151 athletes (108 male and 43 female) were assessed during national championship preseason. All participants were healthy, with no current pain of lower limb injury and no history of previous lower extremity surgery. The mean age, weight and height were 14.21+2.09; 62.75+14.20 and 173.89+13.42, respectively. Assessment of risk factors Gender, age and sport. Main outcome measurements Knee valgus was measured as frontal plane projection angle of the knee (FPPAK) during SLS up to 60° of knee flexion. The mean of three repetitions of SLS from each limb was used for analysis, using SIMI Motion Twinner software. The FPPAK was defined as the connections between ASIS, midpoint of femoral epicondyles and anterior midpoint of the malleolis. Results The mean FPPAK during SLS for right leg was 7.08+4.0 and 8.68+4.2 for left leg. There were no differences between ages and genders. There were significant differences between sides in both modalities (p&lt;0.000).The basketball athletes had lower FPPAK on the left leg when compared with athletes from volleyball (p&lt;0.000). Conclusion All athletes showed an inability to maintain proper alignment during dynamic squat. The differences found between modalities may be linked to the specific technique of each sport and are important to guide an intervention focused on injury prevention.
Effects of Porphyromonas gingivalis on cell cycle progression and apoptosis of primary human chondrocytes
Authors: N Pischon, E Rohner, A Hocke, P N'Guessan, H C Muller, G Matziolis, V Kanitz, P Purucker, B-M Kleber, J-P Bernimoulin, G Burmester, F Buttgereit, J Detert
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> It has been suggested that bacterial infections have a role in the pathogenesis of rheumatoid arthritis (RA). <i>P gingivalis</i>, a Gram-negative, anaerobic rod, is one of the major pathogens associated with periodontal disease. <h3>Objective:</h3> To examine <i>P gingivalis</i> infection and its effects on cell cycle progression and apoptosis of human articular chondrocytes. <h3>Methods:</h3> Primary human chondrocytes cultured in monolayers were challenged with <i>P gingivalis</i>. Infection and invasion of <i>P gingivalis</i> into chondrocytes was analysed by scanning electron microscopy, double immunofluorescence and by antibiotic protection and invasion assay. Cell cycle progression of infected chondrocytes was evaluated by flow cytometry. Also, cell apoptosis was visualised by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) of DNA strand breaks and by western blot analysis. <h3>Results:</h3> Data showed that <i>P gingivalis</i> could adhere and infect primary human chondrocytes. After chondrocyte infection, intracellular localisation of <i>P gingivalis</i> was noted. Flow cytometry analyses demonstrated affected cell cycle progression, with an increase of the G<sub>1</sub> phase and a significant decrease of the G<sub>2</sub> phase after infection. In addition, increased apoptosis of <i>P gingivalis</i>-infected chondrocytes was visualised by TUNEL assay and by upregulation of caspase-3 protein expression. <h3>Conclusion:</h3> These data demonstrate that <i>P gingivalis</i> infects primary human chondrocytes and affects cellular responses, which might contribute to the tissue damage seen in the pathogenesis of rheumatoid arthritis.