tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer
Authors: W. Kievit, M.J. Bolster, G.J. van der Wilt, P. Bult, F.B.J.M. Thunnissen, J. Meijer, L.J.A. Strobbe, J.H.G. Klinkenbijl, T. Wobbes, E.M.M. Adang, L.V.A.M. Beex, V.C.G. Tjan-Heijnen
Journal: Annals of Oncology (2005)
PWE-005 Is Investigation of the Colonic Lumen Necessary after CT Diagnosis of Acute Diverticulitis?
Authors: A Tan, C Newman
Journal: Gut (2013)

<h3>Introduction</h3> Traditionally, it is recommended that the colon be evaluated after an episode of acute diverticulitis to exclude underlying pathologies such as malignancy. However, the necessity of this has been questioned in this era of frequent use of contrast-enhanced multidetector computed tomography (CT), which itself is a moderately sensitive test for colorectal cancer, to diagnose acute diverticulitis. This study aimed to determine the yield of malignancy from subsequent follow-up investigations or treatments in patients after an episode of CT-proven acute diverticulitis. <h3>Methods</h3> This was a retrospective study of patients with acute diverticulitis as diagnosed on CT at a moderately-sized district general hospital between January 2007 and December 2011. Uncomplicated diverticulitis was defined as the presence of colonic diverticular disease with localised colonic wall thickening and/or inflammation of pericolic fat. Complicated diverticulitis was defined as the additional presence of abscess, obstruction, fistula or evidence of perforation. <h3>Results</h3> A total of 64 patients were diagnosed with acute diverticulitis on contrast-enhanced CT. Thirty-five patients had uncomplicated diverticulitis and 29 patients had complicated diverticulitis. The follow-up of patients with uncomplicated disease were as follows: flexible sigmoidoscopy (10), colonoscopy (4), CT colonography (2) and barium enema (4). Two patients underwent surgery. All investigations or treatments confirmed diverticular disease. None of them showed underlying malignancy. Incidental findings at the diseased sites were detected in 4 patients. Three of them had polyps and one had an aphthous ulcer. Of the patients with polyps, one had a tubular adenoma greater than 10mm, one had a 2mm tubular adenoma with low-grade dysplasia and one had an inflammatory polyp. The biopsy of the patient with the ulcer was normal. The remaining 13 patients had no follow-up and none of them were known to have returned with malignancy. The follow-up of patients with complicated disease were as follows: flexible sigmoidoscopy (9), colonoscopy (4), CT colonography (1) and barium enema (5). Six patients had surgery. All investigations or treatments confirmed diverticular disease with no evidence of underlying malignancy. A patient who underwent surgery incidentally had hyperplastic polyps in the sigmoid colon specimen. Four patients had no follow-up and none of them were known to have developed malignancy. <h3>Conclusion</h3> The yield of malignancy as an underlying pathology was nil in both cohorts. Routine investigation of the colonic lumen after an episode of acute diverticulitis in this era of widespread CT use may not be necessary in the absence of other sinister indications. Limited resources may be better utilised for other patients with greater risk of colorectal cancer. <h3>Disclosure of Interest</h3> None Declared
Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas
Authors: Ajay K. Yadav
Journal: JAMA (2009)

Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood.To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas.Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells.Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis.Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion).Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene.
Pulmonary haemodynamics and function immediately after canine left lower lobe preservation.
Authors: J A Bardin, P M Taft, N A Halasz
Journal: Thorax (1978)

After temporary reimplantation of the left lower lobe in dogs, the effects of various preservation techniques on the canine lung were assessed. Vascular resistance, shunt fraction, weight gain, and airway pressure were found to reflect and predict the effectiveness of various preservation techniques compared with reported survival data.
L-Selectin–Mediated Neutrophil Recruitment in Experimental Rodent Aneurysm Formation
Authors: Kevin K. Hannawa, Jonathan L. Eliason, Derek T. Woodrum, Charles G. Pearce, Karen J. Roelofs, Vladimir Grigoryants, Matthew J. Eagleton, Peter K. Henke, Thomas W. Wakefield, Daniel D. Myers, James C. Stanley, Gilbert R. Upchurch
Journal: Circulation (2005)

Background— This investigation tested the hypothesis that L-selectin is important in experimental abdominal aortic aneurysm (AAA) formation in rodents. Methods and Results— Rat abdominal aortas were perfused with saline (control) or porcine pancreatic elastase and studied on postperfusion days 1, 2, 4, 7, and 14 (n=5 per treatment group per day). Neutrophil (polymorphonucleur leukocyte, PMN) and macrophage counts per high-powered field (HPF) were performed on fixed sections. L-selectin expression and protein levels in aortic tissue were determined by polymerase chain reaction and Western blot, respectively. Elastase-perfused aortic diameters were significantly increased compared with control aortas at all time points except day 1 ( P &lt;0.05). PMN counts significantly increased in elastase-perfused aortas compared with control aortas at days 1, 2, and 4, reaching maximum levels at day 7 (40.8 versus 0.3 PMNs/HPF, P =0.001). L-selectin mRNA expression in elastase-perfused aortas was 18 ( P =0.018), 17 ( P &lt;0.001), and 8 times ( P =0.02) times greater than control aortas at days 1, 2, and 4, respectively. Western blot demonstrated a significant 69% increase in L-selectin protein at day 7 in elastase- as compared with saline-perfused aortas ( P =0.005). Subsequent experiments involved similar studies on postperfusion days 4, 7, and 14 of aortas from C57BL/6 wild-type (WT) mice (n=21) and L-selectin–knockout (LKO) mice (n=19). LKO mice had significantly smaller aortic diameters at day 14 as compared with WT mice (88% versus 123%, P =0.02). PMN counts were significantly greater in elastase-perfused WT mouse aortas as compared with LKO mouse aortas at day 4 after perfusion (12.8 versus 4.8 PMNs/HPF, P =0.02). Macrophage counts were significantly greater at all time points after perfusion in elastase-perfused WT mouse aortas compared with elastase-perfused LKO mouse aortas, with a maximum difference at day 7 after perfusion (13.3 versus 0.5 macrophages/HPF, P &lt;0.001). Conclusion— L-selectin–mediated neutrophil recruitment may be a critical early step in AAA formation.
High‐Density Polymer Microarrays: Identifying Synthetic Polymers that Control Human Embryonic Stem Cell Growth
Authors: Anne Hansen, Heidi K. Mjoseng, Rong Zhang, Michail Kalloudis, Vasileios Koutsos, Paul A. de Sousa, Mark Bradley
Journal: Advanced Healthcare Materials (2013)

The fabrication of high-density polymer microarray is described, allowing the simultaneous and efficient evaluation of more than 7000 different polymers in a single-cellular-based screen. These high-density polymer arrays are applied in the search for synthetic substrates for hESCs culture. Up-scaling of the identified hit polymers enables long-term cellular cultivation and promoted successful stem-cell maintenance. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Body composition and physiological characteristics of law enforcement officers.
Authors: D L Spitler, G Jones, J Hawkins, L Dudka
Journal: British Journal of Sports Medicine (1987)

The physical work capacity, body composition, and physiological characteristics of 12 law enforcement officers (9 males, 3 females) were measured. Subjects included a representative sample from the occupational categories of detective, staff, investigative and patrol officer. Mean maximal oxygen uptake of the men was 42.1 +/- 8.9 ml.kg-1min-1 with mean values of 41.5 +/- 8.7 ml.kg-1min-1 for the women. Measurement of body composition indicated an average of 24.4 +/- 7.1% body fat for the men and 30.9 +/- 1.2% for the women. Muscular power, strength, and endurance as measured by isolated limb flexion-extension movement and fitness test performance was considered average with no excessive bilateral differences. The results of this study were compared with other investigations of law enforcement officers of similar age groups. The officers displayed average or above health and physical fitness scores for their age classification and were able to complete all police task-oriented tests.
Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new congenital photosensitivity syndrome
Authors: None Anstey, None Ryan, None Rhodes, None Charman, None Arlett, None Tyrrell, None Taylor, None Pearse
Journal: British Journal of Dermatology (1999)

Photosensitivity has recently been reported as a feature of the Smith–Lemli–Opitz syndrome (SLO). The aim of this study was to establish the photobiological features of this disorder and to examine the hypothesis that the photosensitivity is caused by the high levels of 7-dehydrocholesterol found in SLO. All known cases of SLO in the U.K. were reviewed and clinical details of photosensitivity were recorded in detail. The action spectrum of the photosensitive eruption was defined by monochromator light testing. Thirteen of the 23 subjects (57%) had severe photosensitivity, and in 10 there was no photosensitivity. No correlation was identified between levels of 7-dehydrocholesterol and severity of photosensitivity, suggesting that the photosensitivity in SLO is not caused by a direct phototoxic effect mediated by 7-dehydrocholesterol. A novel pattern of photosensitivity was observed, with onset of a sunburn-like erythema on sun-exposed skin within minutes of sun exposure, which persisted in most cases for up to 24–48 h before fading. Monochromator light testing in three subjects showed an ultraviolet (UV) A-mediated photosensitivity eruption with greatest photosensitivity at 350 nm. Photosensitivity is a common and prominent feature of SLO and appears to be UVA-mediated. Elucidation of its biochemical basis may provide insight into normal cutaneous protective mechanisms against UVA-induced photodamage, and also sun sensitivity in general.
Cortactin Is an Essential Regulator of Matrix Metalloproteinase Secretion and Extracellular Matrix Degradation in Invadopodia
Authors: Emily S. Clark, Amy S. Whigham, Wendell G. Yarbrough, Alissa M. Weaver
Journal: Cancer Research (2007)

Abstract Invadopodia are branched actin-rich structures associated with extracellular matrix (ECM) degradation that collectively form the invasive machinery of aggressive cancer cells. Cortactin is a prominent component and a specific marker of invadopodia. Amplification of cortactin is associated with poor prognosis in head and neck squamous cell carcinomas (HNSCC), possibly because of its activity in invadopodia. Although the role of cortactin in invadopodia has been attributed to signaling and actin assembly, it is incompletely understood. We made HNSCC cells deficient in cortactin by RNA interference knockdown methods. In these cortactin knockdown cells, invadopodia were reduced in number and lost their ability to degrade ECM. In the reverse experiment, overexpression of cortactin dramatically increased ECM degradation, far above and beyond the effect on formation of actin/Arp3–positive invadopodia puncta. Secretion of matrix metalloproteinases (MMP) MMP-2 and MMP-9, as well as plasma membrane delivery of MT1-MMP correlated closely with cortactin expression levels. MMP inhibitor treatment of control cells mimicked the cortactin knockdown phenotype, with abolished ECM degradation and fewer invadopodia, suggesting a positive feedback loop in which degradation products from MMP activity promote new invadopodia formation. Collectively, these data suggest that a major role of cortactin in invadopodia is to regulate the secretion of MMPs and point to a novel mechanism coupling dynamic actin assembly to the secretory machinery, producing enhanced ECM degradation and invasiveness. Furthermore, these data provide a possible explanation for the observed association between cortactin overexpression and enhanced invasiveness and poor prognosis in HNSCC patients. [Cancer Res 2007;67(9):4227–35]
Effects of acute hypovolaemia by furosemide on tracheal transepithelial potential difference and mucus in dogs
Authors: N.K. Nakagawa, F. Donato-Júnior, C.S. Kondo, M. King, J.O.C. Auler-Júnior, P.H.N. Saldiva, G. Lorenzi-Filho
Journal: European Respiratory Journal (2004)

Furosemide is a potent diuretic that affects water transfer across the respiratory epithelium, which is closely related to the transepithelial potential difference (PD). Water is a critical factor that determines mucus transport; an important lung defence mechanism that removes particles and microorganisms from the respiratory system. The aim of the present study was to investigate the acute effects of furosemide and hypovolaemia on tracheal PD and mucus properties. A total of 36 male mixed-breed dogs were submitted to anaesthesia, mechanical ventilation and haemodynamic monitoring. They were randomly assigned to three groups consisting of: a control group, a furosemide (40 mg i.v. ) + hypovolaemia group, and a furosemide (40 mg i.v. ) + volume replacement group. Tracheal PD and mucus samples were collected at time 0, 1 and 2 h after intervention. Mucus properties were analysed by means of a magnetic microrheometer and in vitro mucociliary transportability on the frog palate. Compared to controls, furosemide decreased PD to intermediate values, and only significantly when associated with hypovolaemia (−13±5 and −8±2 mV, time 0 and 2 h, respectively). In addition to the direct effect of furosemide, these results indicate that hypovolaemia also affects ion transport in the tracheal membrane. Furosemide and hypovolemia have no acute effects on respiratory mucus properties.
CDC25B Mediates Rapamycin-Induced Oncogenic Responses in Cancer Cells
Authors: Run-qiang Chen, Qing-kai Yang, Bing-wen Lu, Wei Yi, Greg Cantin, Yan-ling Chen, Colleen Fearns, John R. Yates, Jiing-Dwan Lee
Journal: Cancer Research (2009)

Because the mammalian target of rapamycin (mTOR) pathway is commonly deregulated in human cancer, mTOR inhibitors, rapamycin and its derivatives, are being actively tested in cancer clinical trials. Clinical updates indicate that the anticancer effect of these drugs is limited, perhaps due to rapamycin-dependent induction of oncogenic cascades by an as yet unclear mechanism. As such, we investigated rapamycin-dependent phosphoproteomics and discovered that 250 phosphosites in 161 cellular proteins were sensitive to rapamycin. Among these, rapamycin regulated four kinases and four phosphatases. A siRNA-dependent screen of these proteins showed that AKT induction by rapamycin was attenuated by depleting cellular CDC25B phosphatase. Rapamycin induces the phosphorylation of CDC25B at Serine375, and mutating this site to Alanine substantially reduced CDC25B phosphatase activity. Additionally, expression of CDC25B (S375A) inhibited the AKT activation by rapamycin, indicating that phosphorylation of CDC25B is critical for CDC25B activity and its ability to transduce rapamycin-induced oncogenic AKT activity. Importantly, we also found that CDC25B depletion in various cancer cell lines enhanced the anticancer effect of rapamycin. Together, using rapamycin phosphoproteomics, we not only advance the global mechanistic understanding of the action of rapamycin but also show that CDC25B may serve as a drug target for improving mTOR-targeted cancer therapies.
Inhibition of human colony-forming-unit erythroid by tumor necrosis factor requires accessory cells.
Authors: R T Means, E N Dessypris, S B Krantz
Journal: Journal of Clinical Investigation (1990)

Recombinant tumor necrosis factor (rTNF) inhibits erythropoiesis in vivo and in vitro. To study the mechanism of this inhibition, the effect of rTNF on highly purified human CFU-erythroid (E) (mean purity 63.5%), which were generated from peripheral blood burst-forming units-erythroid (BFU-E), was compared to its effect on unpurified human marrow CFU-E (mean purity 0.21%). Although growth of colonies from marrow CFU-E was inhibited by rTNF, no significant effect on purified BFU-E-derived CFU-E colony growth was found. Removal of accessory marrow cells by soy bean agglutinin (SBA) ablated the inhibition of marrow CFU-E colonies by rTNF. Inhibition of colony growth was then restored by adding back SBA+ cells, but not by adding T lymphocytes or adherent cells. Conditioned medium prepared from bone marrow mononuclear cells stimulated by rTNF inhibited the growth of colonies from highly purified BFU-E derived CFU-E resistant to direct inhibition by rTNF. These findings indicate that rTNF does not directly inhibit CFU-E, but requires accessory cells to decrease erythropoiesis. These accessory cells reside in the SBA+ cell fraction, but are neither T cells nor adherent cells. Therefore, in order to produce anemia, TNF must induce release or production of a factor that directly inhibits erythroid colony growth.
MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks
Authors: Beth A. Helmink, Andrea L. Bredemeyer, Baeck-Seung Lee, Ching-Yu Huang, Girdhar G. Sharma, Laura M. Walker, Jeffrey J. Bednarski, Wan-Ling Lee, Tej K. Pandita, Craig H. Bassing, Barry P. Sleckman
Journal: The Journal of Experimental Medicine (2009)

The Mre11-Rad50-Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of antigen receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during lymphocyte antigen receptor gene assembly.
Administrative Data Algorithms to Identify Second Breast Cancer Events Following Early-Stage Invasive Breast Cancer
Authors: Jessica Chubak, Onchee Yu, Gaia Pocobelli, Lois Lamerato, Joe Webster, Marianne N. Prout, Marianne Ulcickas Yood, William E. Barlow, Diana S. M. Buist
Journal: JNCI Journal of the National Cancer Institute (2012)

Studies of breast cancer outcomes rely on the identification of second breast cancer events (recurrences and second breast primary tumors). Cancer registries often do not capture recurrences, and chart abstraction can be infeasible or expensive. An alternative is using administrative health-care data to identify second breast cancer events; however, these algorithms must be validated against a gold standard. We developed algorithms using data from 3152 women in an integrated health-care system who were diagnosed with stage I or II breast cancer in 1993–2006. Medical record review served as the gold standard for second breast cancer events. Administrative data used in algorithm development included procedures, diagnoses, prescription fills, and cancer registry records. We randomly divided the cohort into training and testing samples and used a classification and regression tree analysis to build algorithms for classifying women as having or not having a second breast cancer event. We created several algorithms for researchers to use based on the relative importance of sensitivity, specificity, and positive predictive value (PPV) in future studies. The algorithm with high specificity and PPV had 89% sensitivity (95% confidence interval [CI] = 84% to 92%), 99% specificity (95% CI = 98% to 99%), and 90% PPV (95% CI = 86% to 94%); the high-sensitivity algorithm had 96% sensitivity (95% CI = 93% to 98%), 95% specificity (95% CI = 94% to 96%), and 74% PPV (95% CI = 68% to 78%). Algorithms based on administrative data can identify second breast cancer events with high sensitivity, specificity, and PPV. The algorithms presented here promote efficient outcomes research, allowing researchers to prioritize sensitivity, specificity, or PPV in identifying second breast cancer events.