tbuckley/cabot-search huggingface dataset:
Association of type XI collagen genes with chronic Achilles tendinopathy in independent populations from South Africa and Australia
Authors: Melanie Hay, Jon Patricios, Robert Collins, Andy Branfield, Jill Cook, Christopher J Handley, Alison V September, Michael Posthumus, Malcolm Collins
Journal: British Journal of Sports Medicine (2013)

Type XI collagen, which is expressed in developing tendons and is encoded by the COL11A1, COL11A2 and COL2A1 genes, shares structural and functional homology with type V collagen, which plays an important role in collagen fibril assembly. We investigated the association of these three polymorphisms with Achilles tendinopathy (AT) and whether these polymorphisms interact with COL5A1 to modulate the risk of AT.184 participants diagnosed with chronic AT (TEN) and 338 appropriately matched asymptomatic controls (CON) were genotyped for the three polymorphisms.Although there were no independent associations with AT, the TCT pseudohaplotype constructed from rs3753841 (T/C), rs1676486 (C/T) and rs1799907 (T/A) was significantly over-represented (p=0.006) in the TEN (25.9%) compared with the CON (17.1%) group. The TCT(AGGG) pseudohaplotypes constructed using these type XI collagen polymorphisms and the functional COL5A1 rs71746744 (-/AGGG) polymorphism were also significantly over-represented (p<0.001) in the TEN (25.2%) compared with the CON (9.1%) group.The genes encoding structural and functionally related type XI (COL11A1 and COL11A2) and type V (COL5A1) collagens interact with one another to collectively modulate the risk for AT. Although there are no immediate clinical applications, the results of this study provide additional evidence that interindividual variations in collagen fibril assembly might be an important molecular mechanism in the aetiology of chronic AT.
Secular Trends in Treatment and Control of Type 2 Diabetes in an American Indian Population: A 30-Year Longitudinal Study
Authors: Helen C. Looker, Jonathan Krakoff, Vickie Andre, Kathy Kobus, Robert G. Nelson, William C. Knowler, Robert L. Hanson
Journal: Diabetes Care (2010)

OBJECTIVE Treatment guidelines for diabetes have become increasingly stringent as most research shows that more aggressive intervention reduces the risks for complications. Community data on the effect of these interventions are lacking. RESEARCH DESIGN AND METHODS Changes in the pharmacologic treatment of diabetes, blood pressure, and cholesterol in adults with diabetes were analyzed in a longitudinal population-based study of American Indians from 10 independent 3-year time intervals between 1975 and 2004. Trends in drug use were assessed by logistic regression models and trends in glycemia, blood pressure, and cholesterol were assessed by linear models. RESULTS Among the study participants, the use of any medicine for the treatment of diabetes increased from 53% in 1975–1978 to 67% in 2002–2004, Ptrend &amp;lt; 0.0001. The use of insulin as a single agent declined, and the use of combinations of insulin and oral agents increased. In 1990–1992, 23% of subjects had an A1C &amp;lt;7% and by 2002–2004, the proportion had increased to 33%, Ptrend &amp;lt; 0.0001. The use of anti-hypertensive medicine increased from 21% in 1975–1977 to 58% in 2002–2004, Ptrend &amp;lt; 0.0001, coincident with a decline in mean systolic blood pressure from 137 mmHg in 1975–1977 to 123 mmHg in 2002–2004, Ptrend &amp;lt; 0.0001. The use of lipid-lowering medicine also increased with an accompanying increase in HDL and a decrease in non-HDL cholesterol concentration. CONCLUSIONS Major changes in community treatment patterns for diabetes and related conditions coincided with improvements in glycemia, blood pressure, and cholesterol.
Intrinsic Myofilament Alterations Underlying the Decreased Contractility of Stunned Myocardium
Authors: Wei Dong Gao, Yongge Liu, Ronald Mellgren, Eduardo Marban
Journal: Circulation Research (1996)

We investigated the mechanism of the decreased myofilament Ca2+ responsiveness in stunned myocardium. The steady state force-[Ca2+] relationship was measured before and after skinning in thin ventricular trabeculae from control or stunned (20 minutes of ischemia, 20 minutes of reperfusion) rat hearts.[Ca2+]i was determined using microinjected fura 2 salt in intact muscles, whereas the myofilaments of chemically skinned trabeculae were activated directly with solutions of varied [Ca2+]. Maximal Ca2+- activated force (F max) before and after skinning was identical within either the control or stunned groups but was markedly depressed in both groups of stunned trabeculae (P < .001)). After ischemia and reperfusion, the [Ca2+] required for 50% of maximal activation (Ca50) was increased in both intact (control, 0.60 +/- 0.09 micromol/L; stunned, 0.85 +/- 0.09 micromol/L;P < .001) and skinned (control, 1.13 +/- 0.24 micromol/L; stunned 1.39 +/- 0.21 micromol/L; P = .0025) trabeculae. These data indicate that the decreased Ca2+ responsiveness of stunned myocardium is due to intrinsic alterations of the myofilaments. Therefore, we tested the hypothesis that activation of proteases by reperfusion-induced Ca2+ overload decreases the Ca2+ responsiveness of the cardiac myofilaments. Force-[Ca2+] relations were compared before and 5 to 30 minutes after direct exposure of skinned trabeculae to calpain I (18 microgram/mL, 20 minutes at [Ca2+]=10.8 micromol/L), a Ca2+-activated protease that is present in myocardium. Calpain I reduced F max from 94.3 +/- 8.3 to 56 +/- 8.5 mN/mm2 while increasing Ca50 from 0.94 +/- 0.11 to 1.36 +/- 0.21 micromol/L (P < .01). Calpastatin, a specific calpain inhibitor prevented the effects of calpain I on skinned trabeculae. The results show that the reduced Ca2+ responsiveness of stunned myocardium reflects alteration of the myofilaments themselves, not of soluble cytosolic factors, which can be faithfully reproduced by exposure to Ca2+-dependent protease.
Tooth anatomy risk factors influencing root canal working length accessibility
Authors: Lu-Lu Tang, Tuo-qi Sun, Xiao-Jie Gao, Xue Dong Zhou, Ding-Ming Huang
Journal: International Journal of Oral Science (2011)

The aim of this study was to analyze the specific influence of root canal anatomy on the accessibility of working length during root canal therapy. Four hundred seventy‐six root canal therapy cases (amounting to a total of 1 005 root canals) were examined. The anatomy risk factors assessed in each case included: tooth type (tooth location), root canal curvature, and root canal calcification, as well as endodontic retreatment. The investigation examined the correlation between each of these anatomic factors and the working length, with statistical analysis consisting of Chi‐square tests and multiple logistic regression analysis. In an independent factor analysis, tooth type (tooth location), root canal curvature, canal calcification, and endodontic retreatment were determined to be the primary risk factors. In a multiple‐factor regression model, root curvature and canal calcification were found to most significantly influence root canal working length accessibility (P<0.05). Root canal anatomy increases the difficulty of root canal preparation. Appropriate consideration of tooth anatomy will assist in accurate determination of preparation difficulty before instrumentation. This study alerts clinical therapists to anatomical factors influencing the working length accessibility, and allows for a direct estimate of success rate given in situ measurements of tooth factors during the root canal treatment procedure.
Antitumor Efficacy of Edotecarin as a Single Agent and in Combination with Chemotherapy Agents in a Xenograft Model
Authors: Marina Ciomei, Valter Croci, Antonella Ciavolella, Dario Ballinari, Enrico Pesenti
Journal: Clinical Cancer Research (2006)

The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.
Identification of FoxR2 as an Oncogene in Medulloblastoma
Authors: Hideto Koso, Asano Tsuhako, Eli Lyons, Jerrold M. Ward, Alistair G. Rust, David J. Adams, Nancy A. Jenkins, Neal G. Copeland, Sumiko Watanabe
Journal: Cancer Research (2014)

Abstract Medulloblastoma is the most common pediatric brain tumor, and in ∼25% of cases, it is driven by aberrant activation of the Sonic Hedgehog (SHH) pathway in granule neuron precursor (GNP) cells. In this study, we identified novel medulloblastoma driver genes through a transposon mutagenesis screen in the developing brain of wild-type and Trp53 mutant mice. Twenty-six candidates were identified along with established driver genes such as Gli1 and Crebbp. The transcription factor FoxR2, the most frequent gene identified in the screen, is overexpressed in a small subset of human medulloblastoma of the SHH subtype. Tgif2 and Alx4, 2 new putative oncogenes identified in the screen, are strongly expressed in the SHH subtype of human medulloblastoma. Mutations in these two genes were mutually exclusive with mutations in Gli1 and tended to cooccur, consistent with involvement in the SHH pathway. Notably, Foxr2, Tgif2, and Alx4 activated Gli-binding sites in cooperation with Gli1, strengthening evidence that they function in SHH signaling. In support of an oncogenic function, Foxr2 overexpression transformed NIH3T3 cells and promoted proliferation of GNPs, the latter of which was also observed for Tgif2 and Alx4. These findings offer forward genetic and functional evidence associating Foxr2, Tgif2, and Alx4 with SHH subtype medulloblastoma. Cancer Res; 74(8); 2351–61. ©2014 AACR.
The Role Of Qualitative FDG-PET Assessment Using The 5 Point Deauville Scale For Postinduction Response Assessment In Patients With Follicular Lymphoma. A Study From The Fondazione Italiana Linfomi (FIL)
Authors: Stefano Luminari, Annibale Versari, Antonella Franceschetto, Simona Peano, Stephan Chauvie, Fabrizio Bergesio, Carola Boccomini, Alessandra Tucci, Francesco Merli, Chiara Rusconi, Flavia Salvi, Alessandra Dondi, Massimo Federico
Journal: Blood (2013)
Chromosome Painting In Silico in a Bacterial Species Reveals Fine Population Structure
Authors: Koji Yahara, Yoshikazu Furuta, Kenshiro Oshima, Masaru Yoshida, Takeshi Azuma, Masahira Hattori, Ikuo Uchiyama, Ichizo Kobayashi
Journal: Molecular Biology and Evolution (2013)

Identifying population structure forms an important basis for genetic and evolutionary studies. Most current methods to identify population structure have limitations in analyzing haplotypes and recombination across the genome. Recently, a method of chromosome painting in silico has been developed to overcome these shortcomings and has been applied to multiple human genome sequences. This method detects the genome-wide transfer of DNA sequence chunks through homologous recombination. Here, we apply it to the frequently recombining bacterial species Helicobacter pylori that has infected Homo sapiens since their birth in Africa and shows wide phylogeographic divergence. Multiple complete genome sequences were analyzed including sequences from Okinawa, Japan, that we recently sequenced. The newer method revealed a finer population structure than revealed by a previous method that examines only MLST housekeeping genes or a phylogenetic network analysis of the core genome. Novel subgroups were found in Europe, Amerind, and East Asia groups. Examination of genetic flux showed some singleton strains to be hybrids of subgroups and revealed evident signs of population admixture in Africa, Europe, and parts of Asia. We expect this approach to further our understanding of intraspecific bacterial evolution by revealing population structure at a finer scale.
Untreated Type 2 Diabetes and Its Complications Are Associated With Subcortical Infarctions
Authors: Rosebud O. Roberts, Kejal Kantarci, Yonas E. Geda, David S. Knopman, Scott A. Przybelski, Stephen D. Weigand, Ronald C. Petersen, Clifford R. Jack
Journal: Diabetes Care (2010)

OBJECTIVE To investigate the association of type 2 diabetes with subcortical infarctions. RESEARCH DESIGN AND METHODS We investigated this association in subjects with type 2 diabetes (case subjects; n = 93) and without type 2 diabetes (control subjects; n = 186), matched by age, sex, and years of education. Participants were a subset of the Mayo Clinic Study of Aging (median age 79 years) who had undergone magnetic resonance imaging. RESULTS The frequency of subcortical infarctions was 39% in case subjects and 29% in control subjects (odds ratio 1.59 [95% CI 0.91–2.75]). The association was stronger in case subjects without treatment (2.60 [1.11–6.08]) and in case subjects with diabetes-related complications (1.96 [1.02–3.74]) compared with control subjects. CONCLUSIONS These findings suggest that untreated type 2 diabetes and type 2 diabetes with complications are associated with subcortical infarctions.
Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II
Authors: Nicole Le Moual, Anne-Elie Carsin, Valérie Siroux, Katja Radon, Dan Norback, Kjell Torén, Mario Olivieri, Isabel Urrutia, Lucia Cazzoletti, Bénédicte Jacquemin, Geza Benke, Hans Kromhout, Maria C. Mirabelli, Amar J. Mehta, Vivi Schlünssen, Torben Sigsgaard, Paul D. Blanc, Manolis Kogevinas, Josep M. Antó, Jan-Paul Zock
Journal: European Respiratory Journal (2013)

Occupational exposure is a well-recognised modifiable risk factor for asthma, but the relationship between occupational exposure and asthma control has not been studied. We aimed to study this association among working-age adults from the European Community Respiratory Health Survey (ECRHS). Data were available for 7077 participants (mean age 43 years, 45% never-smokers, 5867 without asthma and 1210 with current asthma). Associations between occupational exposure to specific asthmagens and asthma control status (33% with uncontrolled asthma, based on the Global Initiative for Asthma guidelines) were evaluated using logistic and multinomial regressions, adjusted for age, sex and smoking status, with study areas included as a random effect. Statistically significant positive associations were observed between uncontrolled adult-onset asthma and both past 12-month and 10-year exposure to any occupational asthmagens (OR (95% CI) 1.6 (1.0–2.40) and 1.7 (1.2–2.5), respectively); high (1.7 (1.0–2.8) and 1.9 (1.3–2.9), respectively) and low (1.6 (1.0–2.7) and 1.8 (1.2–2.7), respectively) molecular weight agents; and cleaning agents (2.0 (1.1–3.6) and 2.3 (1.4–3.6), respectively), with stronger associations for long-term exposures. These associations were mainly explained by the exacerbation domain of asthma control and no associations were observed between asthmagens and partly controlled asthma. These findings suggest that occupational exposure to asthmagens is associated with uncontrolled adult-onset asthma. Occupational risk factors should be quickly identified to prevent uncontrolled asthma.
c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration
Authors: R Schwabe
Journal: Hepatology (2003)

The c-Jun-N-terminal kinase (JNK) pathway is strongly activated after partial hepatectomy (PH), but its role in hepatocyte proliferation is not known. In this study, JNK activity was blocked with the small molecule inhibitor JNK SP600125 in vivo and in vitro as shown by a reduction of c-Jun phosphorylation, AP-1 DNA binding activity, and c-jun messenger RNA (mRNA) expression. SP600125 inhibited proliferating cell nuclear antigen (PCNA) expression, cyclin D1 mRNA and protein expression and reduced mitotic figures after PH. Survival was reduced significantly 3 days after PH in SP600125-treated versus vehicle-treated rats (3 of 11 vs. 8 of 9, P < .01). In epidermal growth factor (EGF)-treated primary cultures of rat hepatocytes, SP600125 decreased 3H-thymidine uptake, cyclin D1 mRNA and protein expression, and inhibited the EGF-induced transcription of a cyclin D1 promoter-driven reporter gene. The defective regeneration and the decreased survival in SP600125-treated rats did not result from a major increase in apoptosis as shown by normal levels of caspase 3 activity and only slight increases in apoptotic figures. In conclusion, our data show that JNK drives G0 to G1 transition in hepatocytes and that cyclin D1 is a downstream target of the JNK pathway during liver regeneration. (Hepatology 2003;37:824-832.)
NRH:Quinone Oxidoreductase 2-Deficient Mice Are Highly Susceptible to Radiation-Induced B-Cell Lymphomas
Authors: Karim Iskander, Roberto J. Barrios, Anil K. Jaiswal
Journal: Clinical Cancer Research (2009)

NRH:quinone oxidoreductase 2 (NQO2) is known to protect against myelogenous hyperplasia. However, the role of NQO2 in prevention of hematologic malignancies remains unknown. Present studies investigated in vivo role of NQO2 in prevention of myeloproliferative disease and lymphomas.Wild-type and NQO2-null mice were exposed to 0, 1, and 3 Gy gamma-radiation. One year later, the mice were analyzed for the development of myeloproliferative disease and lymphomas. Immunohistochemistry analysis determined the B- and T-cell origin of lymphomas. The mice were also sacrificed at 6 and 48 h after radiation exposure and bone marrow was collected and analyzed for p53, Bax, and B-cell apoptosis. Bone marrow cells were cultured and the rate of degradation of p53 was analyzed.Seventy-two percent NQO2-null mice showed development of B-cell lymphomas in multiple tissues compared with 11% in wild-type mice exposed to 3 Gy gamma-radiation. In contrast, only 22% NQO2-null mice showed myeloproliferation compared with none in wild-type mice. Further analysis revealed that bone marrow from NQO2-null mice contained lower levels of p53 compared with wild-type mice due to rapid degradation of p53. In addition, the exposure to radiation resulted in lower induction of p53 and Bax and decreased B-cell apoptosis in NQO2-null mice.NQO2-null mice are highly susceptible to develop radiation-induced B-cell lymphomas. The lack of significant induction of p53 and Bax and decrease in B-cell apoptosis presumably contributed to the development of lymphomas. NQO2 functions as endogenous factor in prevention against radiation-induced B-cell lymphomas.
E7080, a Multi–Tyrosine Kinase Inhibitor, Suppresses the Progression of Malignant Pleural Mesothelioma with Different Proangiogenic Cytokine Production Profiles
Authors: Kenji Ikuta, Seiji Yano, Van The Trung, Masaki Hanibuchi, Hisatsugu Goto, Qi Li, Wei Wang, Tadaaki Yamada, Hirokazu Ogino, Soji Kakiuchi, Hisanori Uehara, Yoshitaka Sekido, Toshimitsu Uenaka, Yasuhiko Nishioka, Saburo Sone
Journal: Clinical Cancer Research (2009)

Malignant pleural mesothelioma (MPM) is a biologically heterogeneous malignant disease with a poor prognosis. We reported previously that the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, effectively inhibited the progression of VEGF-high-producing (but not VEGF-low-producing) MPM cells in orthotopic implantation models, indicating the need for novel therapeutic strategies to improve the poor prognosis of this disease. Therefore, we focused on the multi-tyrosine kinase inhibitor E7080 and assessed its therapeutic efficacy against MPM cells with different proangiogenic cytokine production profiles.The efficacy of E7080 was assayed in orthotopic implantation of severe combined immunodeficient mouse models with three human MPM cell lines (MSTO-211H, NCI-H290, and Y-MESO-14).With regard to proangiogenic cytokine production profiles, MSTO-211H and Y-MESO-14 cells were MPM cells producing high levels of fibroblast growth factor-2 and VEGF, respectively. NCI-H290 cells produced low levels of fibroblast growth factor-2 and VEGF compared with the other two cell lines. E7080 potently suppressed the phosphorylation of VEGF receptor-2 and FGF receptor 1 and, thus, inhibited proliferation of endothelial cells, but not that of the MPM cell lines, in vitro. Orthotopically inoculated MSTO-211H cells produced only thoracic tumors, whereas NCI-H290 and Y-MESO-14 cells also developed pleural effusions. Treatment with E7080 potently inhibited the progression of these three MPM cell lines and markedly prolonged mouse survival, which was associated with decreased numbers of tumor-associated vessels and proliferating MPM cells in the tumor.These results strongly suggest broad-spectrum activity of E7080 against MPM with different proangiogenic cytokine production profiles in humans.
MAX and MYC: A Heritable Breakup
Authors: Alberto Cascón, Mercedes Robledo
Journal: Cancer Research (2012)

Abstract The overexpression of MYC, which occurs in many tumors, dramatically disrupts the equilibrium between activation and repression of the oncogenic MYC/MYC-associated protein X (MAX)/MAX dimerization protein 1 (MXD1) network, favoring MYC–MAX complexes and thereby impairing differentiation and promoting cell growth. Although for some time it has appeared that MAX is necessary for both the activation and repression of the axis, recent evidence shows that MYC retains considerable biologic function in the absence of MAX. The presence of germline MAX mutations in patients with hereditary pheochromocytoma supports the predominant role of MAX as a negative regulator of the network and suggests that MYC deregulation plays a role in hereditary cancer predisposition. This finding also confirms the importance of impairment of the MYC/MAX/MXD1 axis in the development of aggressive neural tumors, because MYCN overexpression is an established genetic hallmark of malign neuroblastoma, and it is likely that MXI1 plays a relevant role in the development of medulloblastoma and glioblastoma. Finally, the likely malignant behavior of tumors with mutations in MAX points to MYC as a candidate therapeutic target in the treatment of metastatic pheochromocytoma. Cancer Res; 72(13); 3119–24. ©2012 AACR.