tbuckley/cabot-search huggingface dataset:
Conditional ablation of Ikkb inhibits melanoma tumor development in mice
Authors: Jinming Yang, Ryan Splittgerber, Fiona E. Yull, Sara Kantrow, Gregory D. Ayers, Michael Karin, Ann Richmond
Journal: Journal of Clinical Investigation (2010)

Several lines of evidence suggest that tumor cells show elevated activity of the NF-kappaB transcription factor, a phenomenon often resulting from constitutive activity of IkappaB kinase beta (IKKbeta). However, others have found that loss of NF-kappaB activity or IKKbeta is tumor promoting. The role of NF-kappaB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKbeta in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRasV12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkb were protected from HRasV12-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkbeta-mediated NF-kappaB activity.
Frequent biclonality and Ig gene alterations among B cell lymphomas that show multiple histologic forms.
Authors: M H Siegelman, M L Cleary, R Warnke, J Sklar
Journal: The Journal of Experimental Medicine (1985)

Configurations of Ig gene DNA were examined in multiple biopsy specimens from seven cases of human B cell lymphoma that showed histologic differences among the specimens within each case. Analysis by Southern blot hybridizations with DNA probes for each of the three Ig loci revealed that the configurations of DNA within these loci were identical among the specimens in two of the cases. This result indicated the monoclonality of these lymphomas, despite differences in histology between biopsy specimens. In contrast, no common nongermline configurations of Ig gene DNA were detected among multiple biopsies in each of three other cases. Therefore, different histologies correlated with separate clones of proliferating B cells in these cases. In the last two cases, the configurations of light chain gene DNA were the same among biopsies in each case, consistent with a monoclonal origin in both lymphomas. However, differences were detected in the configuration of the heavy chain gene DNA. Analysis with a series of DNA probes of the mu heavy chain region indicated that the differences in the DNA configurations of the heavy chain genes from the biopsies probably arose from postrearrangement deletions of either the switch or constant regions of the mu gene. These studies indicate that, contrary to the conventional belief, individual tumors that contain different histologic types of lymphoma within the same patient frequently arise from separate clones of neoplastic cells. Furthermore, the heavy chain genes of monoclonal tumors may show postrearrangement deletions, often resulting from instability of DNA sequences within or around the mu switch region.
Gene Pathways Associated With Prognosis and Chemotherapy Sensitivity in Molecular Subtypes of Breast Cancer
Authors: Takayuki Iwamoto, Giampaolo Bianchini, Daniel Booser, Yuan Qi, Charles Coutant, Christine Ya-Hui Shiang, Libero Santarpia, Junji Matsuoka, Gabriel N. Hortobagyi, William Fraser Symmans, Frankie A. Holmes, Joyce O’Shaughnessy, Beth Hellerstedt, John Pippen, Fabrice Andre, Richard Simon, Lajos Pusztai
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundWe hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers.
Phase II Trial of Chemoradiation for Organ Preservation in Resectable Stage III or IV Squamous Cell Carcinomas of the Larynx or Oropharynx: Results of Eastern Cooperative Oncology Group Study E2399
Authors: Anthony J. Cmelak, Sigui Li, Meredith A. Goldwasser, Barbara Murphy, Michael Cannon, Harlan Pinto, David I. Rosenthal, Maura Gillison, Arlene A. Forastiere
Journal: Journal of Clinical Oncology (2007)

Taxane-based concurrent chemoradiotherapy (CCR) for head and neck cancers has proven to have a favorable toxicity profile compared with cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable stage III/IVA and IVB larynx and oropharynx (OP) cancer patients.Eligibility required resectable stage T2N+, or T3-T4N0-3M0 biopsy-proven squamous carcinoma, age at least 18 years, PS 0 to 2, good organ function, and no prior chemotherapy or radiation. Treatment was induction paclitaxel 175 mg/m(2) and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by concurrent paclitaxel 30 mg/m(2) every 7 days with 70 Gy if no evidence of tumor progression. Weekly erythropoietin alpha 40 kU was used for suboptimal hemoglobin (< 14 gm/dL men, < 13 gm/dL women). The primary end point was organ preservation (freedom from primary site salvage surgery or primary tumor recurrence).One hundred five of 111 patients (36 larynx, 69 OP) were eligible. Median follow-up was 36.7 months. Ninety-four percent received full-dose radiotherapy and 91% received at least five cycles of concurrent paclitaxel. No patient progressed while receiving chemotherapy. Organ preservation was 81% at 2 years after completion of therapy (larynx 74%, OP 84%). Thirteen patients required primary-site salvage surgery (seven larynx, six OP), and six of these have progressed and died (three larynx, three OP). Thirteen patients developed distant metastases (seven larynx, six OP; P = .02) and 10 of 36 larynx and 11 of 69 OP patients have died as a result of their disease. Two-year survival is 76% (63% larynx v 83% OP).A high organ preservation rate was obtained with this regimen for OP but not for larynx patients. Toxicity was low, and induction chemotherapy did not preclude delivery of concurrent chemoradiotherapy.
Low Ascorbate Levels Are Associated with Increased Hypoxia-Inducible Factor-1 Activity and an Aggressive Tumor Phenotype in Endometrial Cancer
Authors: Caroline Kuiper, Ilona G.M. Molenaar, Gabi U. Dachs, Margaret J. Currie, Peter H. Sykes, Margreet C.M. Vissers
Journal: Cancer Research (2010)

Activation of the transcription factor hypoxia-inducible factor (HIF)-1 allows solid tumors to thrive under conditions of metabolic stress. Because HIF-1 is switched off by hydroxylation reactions that require ascorbate, inadequate intracellular ascorbate levels could contribute to HIF-1 overactivation. In this study, we investigated whether the ascorbate content of human endometrial tumors [known to be driven by HIF-1 and vascular endothelial growth factor (VEGF)] influenced HIF-1 activity and tumor pathology. We measured protein levels of HIF-1alpha and three downstream gene products [glucose transporter 1 (GLUT-1), Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and VEGF], as well as the ascorbate content of tumor and patient-matched normal endometrial tissue samples. HIF-1alpha and its downstream gene products were upregulated in tumor tissue, with the highest levels being present in high-grade tumors. High-grade tumors also had reduced capacity to accumulate ascorbate compared with normal tissue; however, all grades contained tumors with low ascorbate content. Tumors with the highest HIF-1alpha protein content were ascorbate deficient. Low ascorbate levels were also associated with elevated VEGF, GLUT-1, and BNIP3 protein levels and with increased tumor size, and there was a significant association between low tissue ascorbate levels and increased activation of the HIF-1 pathway (P = 0.007). In contrast, tumors with high ascorbate levels had lesser levels of HIF-1 activation. This study shows for the first time a likely in vivo relationship between ascorbate and HIF-1, with low tumor tissue ascorbate levels being associated with high HIF-1 activation and tumor growth.
Patterns of spirometry in bronchiectasis patients and relationship to markers of disease severity and hospitalisation
Authors: Richard Stretton, Lucy Poppelwell, Waleed Salih, James Chalmers, Thomas Fardon
Journal: European Respiratory Journal (2013)

Introduction: Bronchiectasis can be associated with obstructive, restrictive or normal spirometry. Reduced FEV1 is associated more severe disease, but no studies exist comparing these 3 patterns of lung function.

Methods: Data from 89 consecutive patients with HRCT confirmed bronchiectasis was collected and patients classified as having obstructive spirometry (FEV1  70% pred) or normal spirometry.

Results: Patients with obstructive spirometry had more bacterial colonisation, particularly with Pseudomonas aeruginosa (Table 1). There was a trend suggesting more severe bronchiectasis using the modified Reiff score (HRCT disease severity) in patients with obstruction and restriction. Patients with restrictive spirometry had a similar severity of bronchiectasis and hospitalisation rate to patients with airflow obstruction.

View this table:

Table 1





17% of patients with normal spirometry were hospitalised over 2 years, compared to 27.3% of patients with restrictive and 32.6% of patients with obstructive spirometry.

Conclusion: Bronchiectasis can be associated with normal, restrictive or obstructive spirometry. Obstructive and restrictive spirometry are associated more severe disease and a higher frequency of hospital admissions.
Anti-inflammatory Triterpenoid Blocks Immune Suppressive Function of MDSCs and Improves Immune Response in Cancer
Authors: Srinivas Nagaraj, Je-In Youn, Hannah Weber, Cristina Iclozan, Lily Lu, Matthew J. Cotter, Colin Meyer, Carlos R. Becerra, Mayer Fishman, Scott Antonia, Michael B. Sporn, Karen T. Liby, Bhupendra Rawal, Ji-Hyun Lee, Dmitry I. Gabrilovich
Journal: Clinical Cancer Research (2010)

Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore, it would be important to identify effective therapeutic means to modulate these cells.We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models, as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine.CDDO-Me at concentrations of 25 to 100 nmol/L completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSCs but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSCs in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with severe combined immunodeficient-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSCs in peripheral blood but significantly improved the immune response.CDDO-Me abrogated the immune suppressive effect of MDSCs and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
Docetaxel Versus Docetaxel Plus Cisplatin As Front-Line Treatment of Patients With Advanced Non—Small-Cell Lung Cancer: A Randomized, Multicenter Phase III Trial
Authors: Vassilis Georgoulias, Alexandros Ardavanis, Athina Agelidou, Maria Agelidou, Vassilis Chandrinos, Emilia Tsaroucha, Michael Toumbis, Charalambos Kouroussis, Konstantinos Syrigos, Aristidis Polyzos, Nikolaos Samaras, Pavlos Papakotoulas, Charalambos Christofilakis, Nicolaos Ziras, Athanasios Alegakis
Journal: Journal of Clinical Oncology (2004)

To compare the overall survival (OS) of patients with advanced non-small-cell lung cancer (NSCLC) treated with docetaxel plus cisplatin (DC) or docetaxel (D) alone.Chemotherapy-naïve patients with advanced/metastatic NSCLC were randomly assigned to receive either DC (n = 167; docetaxel 100 mg/m(2) on day 1, cisplatin 80 mg/m(2) on day 2, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) 150 microg/m(2)/d on days 3 to 9) or D (n = 152; 100 mg/m(2) on day 1 without rhG-CSF) every 3 weeks.The overall response rates were 36.5% for DC (three complete responses and 58 partial responses) and 21.7% for D (one complete response and 32 partial responses; P =.004). The median OS was 10.5 months (range, 0.5 to 41 months) and 8.0 months (range, 0.5 to 41 months) for DC and D, respectively (P =.200). The 1- and 2-year survival rates were 44% and 19% for DC and 43% and 15% for D, respectively. Median times to tumor progression were 4.0 and 2.5 months for DC and D, respectively (P =.580). Grade 2/3 anemia was significantly higher with DC than with D (33% v 16%; P =.0001). Fifteen (9%) DC and 12 (8%) D patients developed febrile neutropenia. Grade 3/4 nausea/vomiting (P =.0001), diarrhea (P =.007), neurotoxicity (P =.017), and nephroroxicity (P =.006) were significantly more common with DC than with D. There were five treatment-related deaths in the DC group and one in the D (P =.098).DC regimen resulted in a higher response rate but without improvement in median time to tumor progression or OS compared with D. D could be a reasonable front-line chemotherapy for patients who cannot tolerate cisplatin.
Return to play after sports concussion in elite and non-elite athletes?
Authors: M Putukian, M Aubry, P McCrory
Journal: British Journal of Sports Medicine (2009)

Objective: To examine the published literature relating to the difference in concussion management strategies between elite and non-elite athletes. Design: Systematic literature review of concussion management. Intervention: Pubmed, Medline, Psych Info, Cochrane Library and Sport Discus databases were reviewed using the MeSH keywords brain concussion and mild traumatic brain injury, combined with athletic injuries. Each were then refined by adding the keyword “return to play” (RTP). English language and human studies only were assessed. Results: For the Medline search, using “brain concussion” as a keyword, 4319 articles were found; this was decreased to 111 when RTP was used to refine the search. When “mild traumatic brain injury” was used, 2509 articles were found; this decreased to 39 when RTP was used to refine the search. Following initial review, these articles form the basis of the discussion below. Conclusions: The non-elite athlete may not have the same resources available as the elite athlete (such as the presence of trained medical staff during practice and competition, a concussion programme as part of sideline preparedness, the benefit of neuropsychological or postural testing, as well as consultants with expertise in concussion readily available) and as a result will generally be managed more conservatively. Younger athletes often have a greater incidence of concussion with longer recovery time frames; however, they are often managed with less expertise and with limited resources.
Thrombotic thrombocytopenic purpura with the use of efalizumab for psoriasis
Authors: J. Thachil, V. Martlew
Journal: British Journal of Dermatology (2008)

Conflicts of interest: none declared. Sir, Psoriasis is a common, persistent, relapsing inflammatory skin disease associated with significant morbidity. It has recently been recognized as a T‐cell mediated inflammatory disease, where the T lymphocytes infiltrate the dermis and then adhere to keratinocytes to produce a psoriatic plaque. Biological therapies have emerged which are specially designed to block specific molecular steps in the pathogenesis of psoriasis and have been demonstrated to be an effective treatment in moderate to severe chronic plaque psoriasis. One of these drugs, efalizumab, is a humanized monoclonal antibody that blocks T‐cell dependent functions mediated by leucocyte function‐associated antigen‐1. This drug was hitherto considered to have a relatively good safety profile and the development of thrombotic thrombocytopenic purpura (TTP) following its use has not previously been observed. A 28‐year‐old woman first presented with a history of chronic plaque psoriasis affecting scalp and limbs in 2004. She initially had topical treatment but within 4 months she required systemic drugs. Methotrexate was given weekly for 2 years with an initial good response but later she relapsed. There was no satisfactory response to the addition of ciclosporin, and biological therapy was then considered. The Psoriasis Area and Severity Index score at this time was 9 and the Dermatology Life Quality Index was 30. Efalizumab was chosen and administered weekly for 6 weeks. Prior to the seventh weekly dose, a full blood count showed a low haemoglobin concentration (Hb) (5·6 g dL−1), and platelet count (17 × 109 L−1). Her blood film showed fragmented red cells, spherocytes and polychromasia. Lactate dehydrogenase (LDH) was elevated at 2067 U L−1 (normal range < 450 U L−1), haptoglobin was undetectable (< 0·01 U L−1) and the reticulocyte count was increased [148 × 109 L−1 (normal range 20–110 × 109 L−1 for normal Hb)]. A direct antiglobin test was negative and the coagulation profile was normal. She did not have any fever, neurological symptoms or signs or renal impairment. A clinical diagnosis of microangiopathic haemolytic anaemia due to TTP was made with the microangiopathic features of the blood smear and the laboratory features of haemolytic anaemia. Treatment was commenced with daily plasma exchange. Laboratory assays for ADAMTS‐13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) demonstrated very low levels consistent with the diagnosis of TTP. With the daily plasma exchange, the platelet count and LDH normalized within 5 days but the haemoglobin continued to be low with evidence of fragmentation on the peripheral smear. The plasma exchange was continued for another 30 days before the haemoglobin normalized. The ADAMTS‐13 assay had normalized when checked after the treatment with plasma exchange had been discontinued.
Inverse relationship between percentage body weight change and finishing time in 643 forty-two-kilometre marathon runners
Authors: Hassane Zouhal, Carole Groussard, Guenolé Minter, Sophie Vincent, Armel Cretual, Arlette Gratas-Delamarche, Paul Delamarche, Timothy David Noakes
Journal: British Journal of Sports Medicine (2010)

Objective The purpose of this study was to determine the relationship between athletic performance and the change in body weight (BW) during a 42 km marathon in a large cohort of runners. Methods The study took place during the 2009 Mont Saint-Michel Marathon (France). 643 marathon finishers (560 males and 83 females) were studied. The change in BW during the race was calculated from measurements of each runner's BW immediately before and after the race. Results BW loss was 2.3±2.2% (mean±SEM) (p&lt;0.01). BW loss was −3.1±1.9% for runners finishing the marathon in less than 3 h; −2.5±2.1% for runners finishing between 3 and 4 h; and −1.8±2.4% for runners who required more than 4 h to complete the marathon. The degree of BW loss was linearly related to 42 km race finishing time (p&lt;0.0000001). Neither age nor gender influenced BW loss during the race. Conclusions BW loss during the marathon was inversely related to race finishing time in 643 marathon runners and was &gt;3% in runners completing the race in less than 3 h. These data are not compatible with laboratory-derived data suggesting that BW loss greater than 2% during exercise impairs athletic performance. They match an extensive body of evidence showing that the most successful athletes in marathon and ultra-marathon running and triathlon events are frequently those who lose substantially more than 3–4% BW during competition.
Exercise training as an adjunct to asthma management?
Authors: Neil Carroll, Peter Sly
Journal: Thorax (1999)

3‐11 the findings in these studies have been variable and have not addressed the clinical eYcacy of such programmes. The quality of the studies has varied and assessing the eYcacy of such programmes depends on which outcomes are assessed and how these outcomes are measured. It is widely recognised that suitable training regimens increase exercise tolerance and capacity in healthy individuals, with greater improvements usually being seen in the more sedentary subjects. 12 This is generally due to a greater capacity for improvement in non-trained individuals. Improvements in exercise capacity are usually accompanied by a number of physiological adaptations including increased oxygen uptake (V~ O2), reduced ventilatory requirements, reduced cardiac frequency, and a reduction in lactic acid production at any given work load. 13
Design principles of molecular networks revealed by global comparisons and composite motifs.
Authors: Haiyuan Yu, Yu Xia, Valery Trifonov, Mark Gerstein
Journal: Genome biology (2006)

Molecular networks are of current interest, particularly with the publication of many large-scale datasets. Previous analyses have focused on topologic structures of individual networks.Here, we present a global comparison of four basic molecular networks: regulatory, co-expression, interaction, and metabolic. In terms of overall topologic correlation--whether nearby proteins in one network are close in another--we find that the four are quite similar. However, focusing on the occurrence of local features, we introduce the concept of composite hubs, namely hubs shared by more than one network. We find that the three 'action' networks (metabolic, co-expression, and interaction) share the same scaffolding of hubs, whereas the regulatory network uses distinctly different regulator hubs. Finally, we examine the inter-relationship between the regulatory network and the three action networks, focusing on three composite motifs--triangles, trusses, and bridges--involving different degrees of regulation of gene pairs. Our analysis shows that interaction and co-expression networks have short-range relationships, with directly interacting and co-expressed proteins sharing regulators. However, the metabolic network contains many long-distance relationships: far-away enzymes in a pathway often have time-delayed expression relationships, which are well coordinated by bridges connecting their regulators.We demonstrate how basic molecular networks are distinct yet connected and well coordinated. Many of our conclusions can be mapped onto structured social networks, providing intuitive comparisons. In particular, the long-distance regulation in metabolic networks agrees with its counterpart in social networks (namely, assembly lines). Conversely, the segregation of regulator hubs from other hubs diverges from social intuitions (as managers often are centers of interactions).