tbuckley/cabot-search huggingface dataset:
Telomerase Suppression by Chromosome 6 in a Human Papillomavirus Type 16-Immortalized Keratinocyte Cell Line and in a Cervical Cancer Cell Line
Authors: R. D. M. Steenbergen, D. Kramer, C. J. L. M. Meijer, J. M. M. Walboomers, D. A. Trott, A. P. Cuthbert, R. F. Newbold, W. J. I. Overkamp, M. Z. Zdzienicka, P. J. F. Snijders
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: High-risk human papillomavirus (HPV) types play a major role in the development of cervical cancer in vivo and can induce immortalization of primary human keratinocytes in vitro. Activation of the telomere-lengthening enzyme telomerase constitutes a key event in both processes. Because losses of alleles from chromosome 6 and increased telomerase activity have been observed in high-grade premalignant cervical lesions, we analyzed whether human chromosome 6 harbors a putative telomerase repressor locus that may be involved in HPV-mediated immortalization. Methods: Microcell-mediated chromosome transfer was used to introduce chromosomes 6 and 11 to the in vitro generated HPV type 16 (HPV16)-immortalized keratinocyte cell line FK16A and to the in vivo derived HPV16-containing cervical cancer cell line SiHa. Hybrid clones were analyzed for growth characteristics, telomerase activity, human telomerase reverse transcriptase (hTERT) and HPV16 E6 expression, and telomere length. FK16A hybrid clones were also transduced with an hTERT-containing retrovirus to examine the effect of ectopic hTERT expression on growth. Statistical tests were two-sided. Results: Introduction of human chromosome 6 but not of chromosome 11 to both cell lines yielded hybrid cells that demonstrated crisis-like features (i.e., enlarged and flattened morphology, vacuolation, and multinucleation) and underwent growth arrest after a marked lag period. In the chromosome 6 hybrid clones analyzed, telomerase activity and hTERT messenger RNA (mRNA) expression were statistically significantly reduced compared with those in the chromosome 11 hybrid clones (for telomerase activity, P = .004 for the FK16A hybrids and P = .039 for the SiHa hybrids; for hTERT mRNA expression, P = .003 for the FK16A hybrids). The observed growth arrest was associated with telomeric shortening. Ectopic expression of hTERT in FK16A cells could prevent the telomeric shortening-based growth arrest induced by chromosome 6. Conclusions: Chromosome 6 may harbor a repressor of hTERT transcription, the loss of which may be involved in HPV-mediated immortalization.
O <sub>2</sub> Sensing in the Human Ductus Arteriosus
Authors: Evangelos D. Michelakis, Ivan Rebeyka, XiChen Wu, Ali Nsair, Bernard Thébaud, Kyoko Hashimoto, Jason R.B. Dyck, Al Haromy, Gwyneth Harry, Amy Barr, Stephen L. Archer
Journal: Circulation Research (2002)

Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O2 constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O2 alters the function of an O2 sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H2O2), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K+ channels, Kv). O2 constriction was evaluated in 26 human DAs (12 female, aged 9+/-2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O2 cause similar constriction and K+ current inhibition (I(K)). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O2 and 4-AP constriction in DA rings and reduced O2- and 4-AP-sensitive I(K) in DASMCs. Remodeled DAMSCs are depolarized and express less O2-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK(Ca)). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O2. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I(K) and reversing constriction to O2, but not phenylephrine. O2 increases, whereas hypoxia and ETC inhibitors decrease H2O2 production by altering mitochondrial membrane potential (DeltaPsim). H2O2, like O2, inhibits I(K) and depolarizes DASMCs. We conclude that O2 controls human DA tone by modulating the function of the mitochondrial ETC thereby varying DeltaPsim and the production of H2O2, which regulates DASMC Kv channel activity and DA tone.
Ultralow-Dose Micronized 17β-Estradiol and Bone Density and Bone Metabolism in Older Women
Authors: Karen M. Prestwood, Anne M. Kenny, Alison Kleppinger, Martin Kulldorff
Journal: JAMA (2003)

Estrogen therapy is known to prevent osteoporosis, but studies have shown that conventional doses increase adverse events. Whether lower doses, one quarter of standard treatment, prevent bone loss is not known.To examine the effect of 3 years of treatment with 0.25 mg/d of micronized 17beta-estradiol on bone mineral density (BMD) and bone turnover in healthy older postmenopausal women.Randomized, double-blind, placebo-controlled trial conducted from July 24, 1998, through June 14, 2002, at a university general clinical research center in the United States. Healthy, community-dwelling women (N = 167) who were older than 65 years at enrollment.Dosage of 0.25 mg/d of micronized 17beta-estradiol (n = 83) or placebo (n = 84); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months.The BMD of the hip, spine, wrist, and total body measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment.Mean BMD increased at all sites for participants taking low-dose estrogen (17beta-estradiol) compared with placebo (P<.001). Compared with participants receiving placebo, participants taking low-dose estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip; 2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides of type 1 collagen, and bone alkaline phosphatase decreased significantly (P<.001) in participants taking low-dose estrogen compared with placebo. Estradiol, estrone, and sex hormone-binding globulin levels increased in the estrogen-treated group compared with placebo. The adverse effect profile was similar; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups. The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen group and 10 for the placebo group (8 occurred at baseline) (P =.26). There were no reports of breast cancer during the study.In older women, a dosage of 0.25 mg/d of 17beta-estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects. Future studies evaluating the effect of low-dose estrogen on fractures are indicated.
Project Zero Delay: A Process for Accelerating the Activation of Cancer Clinical Trials
Authors: Razelle Kurzrock, Susan Pilat, Marcel Bartolazzi, Dwana Sanders, Jill Van Wart Hood, Stanley D. Tucker, Kevin Webster, Michael A. Mallamaci, Steven Strand, Eileen Babcock, Robert C. Bast
Journal: Journal of Clinical Oncology (2009)

Drug development in cancer research is lengthy and expensive. One of the rate-limiting steps is the initiation of first-in-human (phase I) trials. Three to 6 months can elapse between investigational new drug (IND) approval by the US Food and Drug Administration and the entry of a first patient. Issues related to patient participation have been well analyzed, but the administrative processes relevant to implementing clinical trials have received less attention. While industry and academia often partner for the performance of phase I studies, their administrative processes are generally performed independently, and their timelines driven by different priorities: safety reviews, clinical operations, regulatory submissions, and contracting of clinical delivery vendors for industry; contracts, budgets, and institutional review board approval for academia. Both processes converge on US Food and Drug Administration approval of an IND. In the context of a strategic alliance between M. D. Anderson Cancer Center and AstraZeneca Pharmaceuticals LP, a concerted effort has been made to eliminate delays in implementing clinical trials. These efforts focused on close communications, identifying and matching key timelines, alignment of priorities, and tackling administrative processes in parallel, rather than sequentially. In a recent, first-in-human trial, the study was activated and the first patient identified in 46 days from completion of the final study protocol and about 48 hours after final US Food and Drug Administration IND approval, reducing the overall timeline by about 3 months, while meeting all clinical good practice guidelines. Eliminating administrative delays can accelerate the evaluation of new drugs without compromising patient safety or the quality of clinical research.
Chlamydia pneumoniae inside the atherosclerotic plaque—does it affect plaque inflammation and plaque progression?
Authors: A VANDERWAL
Journal: Cardiovascular Research (2002)

See article by Ezzahiri et al. [5] (pages 269–276) in this issue. 

Exposure to Chlamydia pneumoniae (Cp) is very common among the human population world-wide. Circa 50% of adults bear antibodies to Cp and re-infections occur frequently: most people have 2–3 infections in a lifetime [1]. In Cardiovascular Medicine, interest for such a common opportunistic agent was initiated by insights in seroepidemiologic associations between Cp infection and the risk of atherosclerotic vascular disease, myocardial infarction and stroke [2]. Atherosclerosis has recently been classified as a chronic inflammatory disease [3], so potentially the disease could indeed be initiated or modulated by infectious agents. Still, despite numerous clinical and pathological observations that suggest a link between Cp infection and atherosclerosis (Table 1), the underlying pathophysiological mechanisms are far from elucidated. Is Cp infection capable of initiating atherosclerosis or has it only a contributory role superimposed on effects of classical risk factors? Does systemic Cp infection affect plaque growth/thrombosis through circulating proinflammatory molecules (cytokines, acute phase proteins) or is Cp itself pathologically active inside the atherosclerotic plaque? And, is this of clinical relevance at all? An unsolved issue derived from these questions is whether or not Cp, invading the plaque in parasitized mononuclear cells, could influence the inflammatory response inside atherosclerotic lesions. An item of clinical importance also, since plaque inflammation increases the risk of plaque … 

* Tel.: +31-20-566-5633; fax: +31-20-691-4738. a.c.vanderwal{at}amc.uva.nl
Superior survival of females among 10 538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site
Authors: E. de Vries, T.E.C. Nijsten, O. Visser, E. Bastiaannet, S. van Hattem, M.L. Janssen-Heijnen, J.-W.W. Coebergh
Journal: Annals of Oncology (2007)
Opposite regulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells
Authors: Chaoquan Hu, Limin Huang, Caroline Gest, Xiaodong Xi, Anne Janin, Claudine Soria, Hong Li, He-Lin Lu
Journal: Journal of Hematology & Oncology (2012)

Abstract Background Tissue factor (TF), an initiator of blood coagulation, participates in cancer progression and metastasis. We recently found that inhibition of MAPK/ERK upregulated both full length TF (flTF) and soluble isoform TF (asTF) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells. We explored the possible mechanisms, especially the possible interaction with EGFR and PI3K/Akt pathways. Methods A plasmid containing TF promoter −2174 ~ +128 plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity. In order to study the interaction of these pathways, ERK inhibitor (PD98059), PI3K inhibitors (LY294002, wortmannin), Akt inhibitor (A6730), and EGFR inhibitor (erlotinib) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells, and ovarian cancer OVCAR-3 and SKOV-3 cells. Quantitative PCR and western blot were used to determine TF expression. One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells. Results We show that PI3K inhibitors LY294002, wortmannin and A6730 significantly inhibited TF promoter activity, and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation. In contrast, ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells. The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors. Most interestingly, the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression. Similar results were found with ovarian cancer cells SKOV-3 and OVCAR-3. Furthermore, in MDA-MB-231, mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment. Conclusions This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt-mediated TF expression in breast cancer MDA-MB-231 cells. The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells. Interestingly, we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231. As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells, targeting these signaling components is expected to potentially inhibit TF expression-associated tumor progression.
Climato-economic habitats support patterns of human needs, stresses, and freedoms
Authors: Evert Van de Vliert
Journal: Behavioral and Brain Sciences (2013)

Abstract This paper examines why fundamental freedoms are so unevenly distributed across the earth. Climato-economic theorizing proposes that humans adapt needs, stresses, and choices of goals, means, and outcomes to the livability of their habitat. The evolutionary process at work is one of collectively meeting climatic demands of cold winters or hot summers by using monetary resources. Freedom is expected to be lowest in poor populations threatened by demanding thermal climates, intermediate in populations comforted by undemanding temperate climates irrespective of income per head, and highest in rich populations challenged by demanding thermal climates. This core hypothesis is supported with new survey data across 85 countries and 15 Chinese provinces and with a reinterpretative review of results of prior studies comprising 174 countries and the 50 states in the United States. Empirical support covers freedom from want, freedom from fear, freedom of expression and participation, freedom from discrimination, and freedom to develop and realize one's human potential. Applying the theory to projections of temperature and income for 104 countries by 2112 forecasts that (a) poor populations in Asia, perhaps except Afghans and Pakistanis, will move up the international ladder of freedom, (b) poor populations in Africa will lose, rather than gain, relative levels of freedom unless climate protection and poverty reduction prevent this from happening, and (c) several rich populations will be challenged to defend current levels of freedom against worsening climato-economic livability.
Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations
Authors: Masao Mizuki, Joachim Schwäble, Claudia Steur, Chunaram Choudhary, Shuchi Agrawal, Bülent Sargin, Björn Steffen, Itaru Matsumura, Yuzuru Kanakura, Frank D. Böhmer, Carsten Müller-Tidow, Wolfgang E. Berdel, Hubert Serve
Journal: Blood (2003)
Advanced-Stage Large-Cell Lymphoma in Children and Adolescents: Results of a Randomized Trial Incorporating Intermediate-Dose Methotrexate and High-Dose Cytarabine in the Maintenance Phase of the APO Regimen: A Pediatric Oncology Group Phase III Trial
Authors: Joseph H. Laver, Jacqueline M. Kraveka, Robert E. Hutchison, Myron Chang, James Kepner, Molly Schwenn, Nancy Tarbell, Sunil Desai, Sheila Weitzman, Howard J. Weinstein, Sharon B. Murphy
Journal: Journal of Clinical Oncology (2005)

The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkin's lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol (doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In this study, we assessed the effects of an intense antimetabolite therapy alternating with APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates.From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediate-dose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm, and five patients directly to the APO arm by study design due to CNS involvement. Planned therapy duration was 12 months.The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma, and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or CNS involvement). The IDM/HiDAC arm was associated with more toxicity.The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the lymphoma phenotype. It cannot be excluded that with a higher number of patients, one treatment could prove superior and future studies will build on these data.
Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment
Authors: Muriel Pichavant, Anne-Sophie Charbonnier, Solenne Taront, Anne Brichet, Benoît Wallaert, Joel Pestel, André-Bernard Tonnel, Philippe Gosset
Journal: Journal of Allergy and Clinical Immunology (2005)
The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis?
Authors: Paola de Pablo, Thomas Dietrich, Iain L C Chapple, Michael Milward, Muslima Chowdhury, Peter J Charles, Christopher D Buckley, Patrick J Venables
Journal: Annals of the Rheumatic Diseases (2013)

Background Studies suggest that periodontitis may be a risk factor for rheumatoid arthritis (RA). The purpose of this study was to determine whether periodontitis is associated with autoantibodies characteristic of RA. Methods Serum samples were tested for anti-cyclic citrullinated peptide (CCP), anti-mutated citrullinated vimentin (MCV), anti-citrullinated α-enolase peptide-1 (CEP-1), anti-citrullinated vimentin (cit-vim), anti-citrullinated fibrinogen (cit-fib) and their uncitrullinated forms anti-CParg (negative control for anti-CCP), anti-arginine-containing α-enolase peptide-1 (REP-1), anti-vimentin and anti-fibrinogen antibodies in patients with and without periodontitis, none of whom had RA. Results Periodontitis, compared with non-periodontitis, was associated with a normal frequency of anti-CCP and anti-MCV (∼1%) but a higher frequency of positive anti-CEP-1 (12% vs 3%; p=0.02) and its uncitrullinated form anti-REP-1 (16% vs 2%; p&lt;0.001). Positive antibodies against uncitrullinated fibrinogen and CParg were also more common among those with periodontitis compared to non-periodontitis patients (26% vs 3%; p&lt;0.001, and 9% vs 3%; p=0.06). After adjusting for confounders, patients with periodontitis had 43% (p=0.03), 71% (p=0.002) and 114% (p&lt;0.001) higher anti-CEP-1, anti-REP-1 and anti-fibrinogen titres, compared with non-periodontitis. Non-smokers with periodontitis, compared with non-periodontitis, had significantly higher titres of anti-CEP-1 (103%, p&lt;0.001), anti-REP-1 (91%, p=0.001), anti-vimentin (87%, p=0.002), and anti-fibrinogen (124%, p&lt;0.001), independent of confounders, confirming that the autoantibody response in periodontitis was not due to smoking. Conclusions We have shown that the antibody response in periodontitis is predominantly directed to the uncitrullinated peptides of the RA autoantigens examined in this study. We propose that this loss of tolerance could then lead to epitope spreading to citrullinated epitopes as the autoimmune response in periodontitis evolves into that of presymptomatic RA.
T gamma (T gamma) cells suppress growth of erythroid colony-forming units in vitro in the pure red cell aplasia of B-cell chronic lymphocytic leukemia.
Authors: K F Mangan, G Chikkappa, P C Farley
Journal: Journal of Clinical Investigation (1982)

In vitro studies were performed in two patients with B-cell chronic lymphocytic leukemia who developed pure red cell aplasia (CLL-PRCA). During the active phase of their red cell aplasia, there was a marked reduction in the numbers of erythroid colony-forming units (CFU-E). Unfractionated sera or separated IgG fractions from these patients did not impair CFU-E proliferation from either autologous or allogeneic marrows. Increased numbers of T lymphocytes were present in marrow aspirates of these patients. Analysis of these T cells indicated that 90 and 35%, respectively, bore Fc receptors for IgG (T gamma cells). Removal of T cells by E-rosetting techniques augmented CFU-E growth in CLL-PRCA 10-fold. Similar treatment of normal marrows did not cause similar enhanced growth of CFU-E. Co-cultures of marrow T cells or T gamma cells obtained during the active phase of CLL-PRCA suppressed CFU-E growth from autologous or allogeneic marrows. After achieving drug-induced remission of the PRCA, marrow T cells were no longer inhibitory. In contrast, BFU-E (erythroid burst-forming units) or granulocyte proliferation in diffusion chambers were not suppressed by CLL-PRCA T cells. These findings suggest that the development of PRCA in B-cell CLL may result from suppression of CFU-E proliferation by T gamma cells.
In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study
Authors: G. von Minckwitz, J.-U. Blohmer, G. Raab, A. Löhr, B. Gerber, G. Heinrich, H. Eidtmann, M. Kaufmann, J. Hilfrich, C. Jackisch, I. Zuna, S.D. Costa
Journal: Annals of Oncology (2004)