tbuckley/cabot-search huggingface dataset:
Blockade of Epidermal Growth Factor Receptors Chemosensitizes Breast Cancer Cells through Up-Regulation of Bnip3L
Authors: Pedro J. Real, Adalberto Benito, Jorge Cuevas, Maria T. Berciano, Ana de Juan, Paul Coffer, Javier Gomez-Roman, Miguel Lafarga, Jose M. Lopez-Vega, Jose L. Fernandez-Luna
Journal: Cancer Research (2005)

Abstract Epidermal growth factor receptor-1 (EGFR) and EGFR-2 (HER2) have become major targets for cancer treatment. Blocking antibodies and small-molecule inhibitors are being used to silence the activity of these receptors in different tumors with varying efficacy. Thus, a better knowledge on the signaling pathways activated by EGFR and HER2 may help unravel novel therapeutic targets and molecular markers of response. Here, we show that treatment of breast cancer cell lines with blocking antibodies against EGFR (cetuximab) or HER2 (trastuzumab) promotes the specific induction of proapoptotic Bnip3L and chemosensitization. Moreover, we found that the Bnip3L gene is transcriptionally activated by FoxO3a. Trastuzumab-mediated induction of Bnip3L and nuclear translocation of FoxO3a was also shown in pleural effusion cells from a breast cancer patient. Transfection of breast cancer cells with constitutively active FoxO3a or with Bnip3L promotes sensitization to chemotherapy-induced apoptosis. On the contrary, blockade of Bnip3L expression by a small interfering RNA strategy significantly diminished the chemosensitizing effect of cetuximab. We found also an inverse correlation between EGFR and Bnip3L expression in surgical specimens from patients with breast cancer. Therefore, blockading EGFR or HER2 specifically up-regulates Bnip3L, which is required for chemosensitization of breast cancer cells. This novel pathway provides also the rationale for therapeutic strategies aimed to induce the expression of Bnip3L.
Dynamic genome organization and gene evolution by positive selection in geminivirus (Geminiviridae)
Authors: J. M. Bradeen, M. C. Timmermans, J. Messing
Journal: Molecular Biology and Evolution (1997)

Geminiviruses (Geminiviridae) are a diverse group of plant viruses differing from other known plant viruses in possessing circular, single-stranded DNA. Current classification divides the family into three subgroups, defined in part by genome organization, insect vector, and plant host range. Previous phylogenetic assessments of geminiviruses have used DNA and/or amino acid sequences from the replication-associated and coat protein genes and have relied predominantly on distance analyses. We used amino acid and DNA sequence data from the replication-associated and coat protein genes from 22 geminivirus types in distance and parsimony analyses. Although the results of our analyses largely agree with those reported previously, we could not always predict viral relationships based on genome organization, plant host, or insect vector. Loss of correlation of these traits with phylogeny is likely due to improved sampling of geminivirus types. Unrooted parsimony trees suggest multiple independent origins for the monopartite genome. genome organization is therefore a dynamic character. Estimates of nonsynonymous and synonymous nucleotide substitutions for extant and inferred ancestral sequences were used to evaluate hypotheses that the replication-associated and coat protein sequences evolve to accommodate plant host and insect vector specificities, respectively. Results suggest that plant host specificity does not solely direct replication-associated protein-evolution but that coat protein sequence does evolve in response to insect vector specificity. Genome organization and, possibly, plant host specificity are not reliable taxonomic characters.
Unsanctifying the sanctuary: challenges and opportunities with brain metastases
Authors: S. Puhalla, W. Elmquist, D. Freyer, L. Kleinberg, C. Adkins, P. Lockman, J. McGregor, L. Muldoon, G. Nesbit, D. Peereboom, Q. Smith, S. Walker, E. Neuwelt
Journal: Neuro-Oncology (2015)

While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.
Early life determinants of physical activity in 11 to 12 year olds: cohort study
Authors: Calum Mattocks, Andy Ness, Kevin Deere, Kate Tilling, Sam Leary, Steven N Blair, Chris Riddoch
Journal: BMJ (2007)

<b>Objective</b> To examine factors in early life (up to age 5 years) that are associated with objectively measured physical activity in 11-12 year olds. <b>Design</b> Prospective cohort study. <b>Setting</b> Avon longitudinal study of parents and children, United Kingdom. <b>Participants</b> Children aged 11-12 years from the Avon longitudinal study of parents and children. <b>Main outcome measure</b> Physical activity levels in counts per minute (cpm) and minutes of moderate to vigorous physical activity for seven days measured with a uniaxial actigraph accelerometer. <b>Results</b> Valid actigraph data, defined as at least three days of physical activity for at least 10 hours a day, were collected from 5451 children. Several factors were associated with physical activity at ages 11-12 years. Regression coefficients are compared with the baseline of "none" for categorical variables: maternal brisk walking during pregnancy (regression coefficient 5.0, 95% confidence interval −8.5 to 18.5; cpm for &lt;1 h/wk and ≥2 h/wk of physical activity 17.7, 5.3 to 30.1), maternal swimming during pregnancy (21.5, 10.9 to 32.1 and cpm for &lt;1 h/wk and ≥2 h/wk of physical activity 24.2, 7.8 to 40.7), parents' physical activity when the child was aged 21 months (28.5, 15.2 to 41.8 and cpm of physical activity for either parent active and both parents active 33.5, 17.8 to 49.3), and parity assessed during pregnancy (2.9, −7.6 to 13.4 and cpm of physical activity for 1 and ≥2 parity 21.2, 7.1 to 35.3). <b>Conclusions</b> Few factors in early life predicted later physical activity in 11-12 year olds. Parents' physical activity during pregnancy and early in the child's life showed a modest association with physical activity of the child at age 11-12 years, suggesting that active parents tend to raise active children. Helping parents to increase their physical activity therefore may promote children's activity.
Resistance to Selective BRAF Inhibition Can Be Mediated by Modest Upstream Pathway Activation
Authors: Fei Su, William D. Bradley, Qiongqing Wang, Hong Yang, Lizhong Xu, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, Min Jung Kim, Kerstin Trunzer, Richard J. Lee, Kathleen Schostack, Jade Carter, Thomas Albert, Soren Germer, Jim Rosinski, Mitchell Martin, Mary Ellen Simcox, Brian Lestini, David Heimbrook, Gideon Bollag
Journal: Cancer Research (2011)

A high percentage of patients with BRAF(V600E) mutant melanomas respond to the selective RAF inhibitor vemurafenib (RG7204, PLX4032) but resistance eventually emerges. To better understand the mechanisms of resistance, we used chronic selection to establish BRAF(V600E) melanoma clones with acquired resistance to vemurafenib. These clones retained the V600E mutation and no second-site mutations were identified in the BRAF coding sequence. Further characterization showed that vemurafenib was not able to inhibit extracellular signal-regulated kinase phosphorylation, suggesting pathway reactivation. Importantly, resistance also correlated with increased levels of RAS-GTP, and sequencing of RAS genes revealed a rare activating mutation in KRAS, resulting in a K117N change in the KRAS protein. Elevated levels of CRAF and phosphorylated AKT were also observed. In addition, combination treatment with vemurafenib and either a MAP/ERK kinase (MEK) inhibitor or an AKT inhibitor synergistically inhibited proliferation of resistant cells. These findings suggest that resistance to BRAF(V600E) inhibition could occur through several mechanisms, including elevated RAS-GTP levels and increased levels of AKT phosphorylation. Together, our data implicate reactivation of the RAS/RAF pathway by upstream signaling activation as a key mechanism of acquired resistance to vemurafenib, in support of clinical studies in which combination therapy with other targeted agents are being strategized to combat resistance.
Role of H2O2 in <i>RET/PTC1</i> Chromosomal Rearrangement Produced by Ionizing Radiation in Human Thyroid Cells
Authors: Rabii Ameziane-El-Hassani, Myriem Boufraqech, Odile Lagente-Chevallier, Urbain Weyemi, Monique Talbot, Didier Métivier, Françoise Courtin, Jean-Michel Bidart, Mohammed El Mzibri, Martin Schlumberger, Corinne Dupuy
Journal: Cancer Research (2010)

During childhood, the thyroid gland is one of the most sensitive organs to the carcinogenetic effects of ionizing radiation that may lead to papillary thyroid carcinoma (PTC) associated with RET/PTC oncogene rearrangement. Exposure to ionizing radiation induces a transient "oxidative burst" through radiolysis of water, which can cause DNA damage and mediates part of the radiation effects. H(2)O(2) is a potent DNA-damaging agent that induces DNA double-strand breaks, and consequently, chromosomal aberrations. Irradiation by 5 Gy X-ray increased extracellular H(2)O(2). Therefore, we investigated the implication of H(2)O(2) in the generation of RET/PTC1 rearrangement after X-ray exposure. We developed a highly specific and sensitive nested reverse transcription-PCR method. By using the human thyroid cell line HTori-3, previously found to produce RET/PTC1 after gamma-irradiation, we showed that H(2)O(2), generated during a 5 Gy X-ray irradiation, causes DNA double-strand breaks and contributes to RET/PTC1 formation. Pretreatment of cells with catalase, a scavenger of H(2)O(2), significantly decreased RET/PTC1 rearrangement formation. Finally, RET/PTC chromosomal rearrangement was detected in HTori-3.1 cells after exposure of cells to H(2)O(2) (25 micromol/L), at a dose that did not affect the cell viability. This study shows for the first time that H(2)O(2) is able to cause RET/PTC1 rearrangement in thyroid cells and consequently highlights that oxidative stress could be responsible for the occurrence of RET/PTC1 rearrangement found in thyroid lesions even in the absence of radiation exposure.
Unexplained severe pulmonary hypertension in two brothers
Authors: HJ Puolijoki, KO Niemela, LO Siitonen
Journal: European Respiratory Journal (1990)

Unexplained pulmonary hypertension of nearly simultaneous onset is reported in two brothers, aged 17 and 26 yrs. Echocardiography revealed right ventricular hypertrophy and dilatation, paradoxical septal motion and an enlarged main pulmonary artery. In the right catheterization highly elevated pulmonary arterial pressures (107/58 and 84/46 mmHg) were seen. Doppler echocardiography showed significant leakage of the pulmonary and tricuspid valves in the younger brother, who died suddenly three weeks later. An initial decline in pulmonary arterial systolic pressure was achieved in the older brother by drug therapy. Eight months later, however, the pressure had risen to the pretreatment level. Dyspnoea increased and the patient underwent heart-lung transplantation but subsequently died. In the family study a third brother, father and mother were healthy.
Cellular Uptake and Intracellular Levels of the Bcl-2 Antisense G3139 in Cultured Cells and Treated Patients with Acute Myeloid Leukemia
Authors: Guowei Dai, Kenneth K. Chan, Shujun Liu, Dale Hoyt, Susan Whitman, Marko Klisovic, TianSheng Shen, Michael A. Caligiuri, John Byrd, Michael Grever, Guido Marcucci
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Down-regulation of Bcl-2 by the antisense G3139, currently under clinical evaluations, could restore chemosensitivity in otherwise resistant malignant cells. To date, the mechanism of intracellular accumulation of G3139 following in vivo administration remains to be elucidated. This study aimed to assess whether detectable intracellular concentrations of G3139 are achievable in vivo and how these relate to Bcl-2 down-regulation. Experimental Design: Cellular uptake of G3139 was studied in leukemia myeloid cell lines and blasts collected from treated patients using a newly developed, novel, and highly sensitive ELISA-based assay. Real-time reverse transcription-PCR was used to quantify Bcl-2 mRNA changes in treated cells. Results: The assay was fully validated and showed a limit of quantification of 50 pmol/L. When exposed to 0.33 to 10 μmol/L G3139, K562 cells exhibited intracellular concentrations in the range of 2.1 to 11.4 pmol/mg protein. When G3139 was delivered with cationic lipids, a 10- to 25-fold increase of the intracellular concentrations was observed. There was an accumulation of G3139 in the nuclei, and the ratio of nucleus to cytoplasm was increased 7-fold by cationic lipids. Intracellular concentrations of G3139 were correlated with Bcl-2 mRNA down-regulation. Robust intracellular concentrations of G3139 were achieved in vivo in bone marrow (range, 3.4-40.6 pmol/mg protein) and peripheral blood mononuclear cells (range, 0.47-19.4 pmol/mg protein) from acute myeloid leukemia patients treated with G3139. Conclusions: This is the first evidence that measurable intracellular levels of G3139 are achievable in vivo in acute myeloid leukemia patients and that Bcl-2 down-regulation is likely to depend on the achievable intracellular concentrations rather than on plasma concentrations.
Gene Expression Differences between Colon and Rectum Tumors
Authors: Rebeca Sanz-Pamplona, David Cordero, Antonio Berenguer, Flavio Lejbkowicz, Hedy Rennert, Ramon Salazar, Sebastiano Biondo, Xavier Sanjuan, Miguel A. Pujana, Laura Rozek, Thomas J. Giordano, Ofer Ben-Izhak, Hector I. Cohen, Philip Trougouboff, Jacob Bejhar, Yanina Sova, Gad Rennert, Stephen B. Gruber, Victor Moreno
Journal: Clinical Cancer Research (2011)

Colorectal cancer studies typically include both colon and rectum tumors as a common entity, though this assumption is controversial and only minor differences have been reported at the molecular and epidemiologic level. We conducted a molecular study based on gene expression data of tumors from colon and rectum to assess the degree of similarity between these cancer sites at transcriptomic level.A pooled analysis of 460 colon tumors and 100 rectum tumors from four data sets belonging to three independent studies was conducted. Microsatellite instable tumors were excluded as these are known to have a different expression profile and have a preferential proximal colon location. Expression differences were assessed with linear models, and significant genes were identified using adjustment for multiple comparisons.Minor differences at a gene expression level were found between tumors arising in the proximal colon, distal colon, or rectum. Only several HOX genes were found to be associated with tumor location. More differences were found between proximal and distal colon than between distal colon and rectum.Microsatellite stable colorectal cancers do not show major transcriptomic differences for tumors arising in the colon or rectum. The small but consistent differences observed are largely driven by the HOX genes. These results may have important implications in the design and interpretation of studies in colorectal cancer.
Metabolic effects of troglitazone therapy in type 2 diabetic, obese, and lean normal subjects.
Authors: J P Frias, J G Yu, Y T Kruszynska, J M Olefsky
Journal: Diabetes Care (2000)

OBJECTIVE: To characterize metabolic effects of troglitazone in type 2 diabetic, obese, and lean subjects, and examine the effects of troglitazone 2-3 weeks after discontinuation. RESEARCH DESIGN AND METHODS: Nine type 2 diabetic, nine obese, and nine lean subjects underwent baseline metabolic studies including an 8-h meal-tolerance test (MTT) and a 5-h glucose clamp. Subjects then received troglitazone (600 mg/day) for 12 weeks and subsequently had repeat metabolic studies. Diabetic subjects remained off hypoglycemic agents for 2-3 weeks and then underwent a 5-h glucose clamp. RESULTS: In diabetic subjects, fasting plasma glucose was reduced (P&amp;lt;0.05) and insulin-stimulated glucose disposal (Rd) was enhanced by treatment (P&amp;lt;0.02). The area under the MTT 8-h plasma glucose curve declined with therapy (P&amp;lt;0.001), and its change was positively correlated with the improvement in Rd (r = 0.75, P&amp;lt;0.05). There was also a positive correlation between the change in fasting hepatic glucose output (HGO) and the change in fasting plasma glucose with treatment (r = 0.92, P&amp;lt;0.001). Discontinuation of therapy for 2-3 weeks did not significantly affect fasting plasma glucose or insulin-stimulated glucose Rd. In obese subjects, insulin-stimulated glucose Rd improved with therapy (P&amp;lt;0.001), allowing for maintenance of euglycemia by lower plasma insulin concentrations (P&amp;lt;0.05). In lean subjects, an increase in fasting HGO (P&amp;lt;0.001) and glucose clearance (P&amp;lt;0.01) was observed. CONCLUSIONS: Troglitazone lowers fasting and postprandial plasma glucose in type 2 diabetes by affecting both fasting HGO and peripheral insulin sensitivity. Its effects are evident 2-3 weeks after discontinuation. In obese subjects, its insulin sensitizing effects suggest a role for its use in the primary prevention of type 2 diabetes.
Parity, Lactation, and Breast Cancer Subtypes in African American Women: Results from the AMBER Consortium
Authors: Julie R. Palmer, Emma Viscidi, Melissa A. Troester, Chi-Chen Hong, Pepper Schedin, Traci N. Bethea, Elisa V. Bandera, Virginia Borges, Craig McKinnon, Christopher A. Haiman, Kathryn Lunetta, Laurence N. Kolonel, Lynn Rosenberg, Andrew F. Olshan, Christine B. Ambrosone
Journal: JNCI Journal of the National Cancer Institute (2014)

African American (AA) women have a disproportionately high incidence of estrogen receptor–negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns also differ by race/ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes. Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors. ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation. The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality.
Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma
Authors: A. Palumbo, F. Gay, S. Bringhen, A. Falcone, N. Pescosta, V. Callea, T. Caravita, F. Morabito, V. Magarotto, M. Ruggeri, I. Avonto, P. Musto, N. Cascavilla, B. Bruno, M. Boccadoro
Journal: Annals of Oncology (2008)
Urinary Cystatin C and Tubular Proteinuria Predict Progression of Diabetic Nephropathy
Authors: Sang Soo Kim, Sang Heon Song, In Joo Kim, Yun Kyung Jeon, Bo Hyun Kim, Ihm Soo Kwak, Eun Kyung Lee, Yong Ki Kim
Journal: Diabetes Care (2012)

OBJECTIVE The aim of this study was to evaluate the association of urinary cystatin C, a tubular damage marker, with the progression of type 2 diabetic nephropathy. RESERCH DESIGN AND METHODS The baseline values of serum and urinary cystatin C were measured as primary parameters and those of urinary nonalbumin protein (NAP) were measured as secondary parameters. In this prospective observational study, a total of 237 type 2 diabetic patients were followed up for 29 months (13–44 months). RESULTS Both the urinary cystatin C-to-creatinine ratio (CCR) and NAP-to-creatinine ratio (NAPCR) were significantly different according to the degree of albuminuria. Both markers had strongly positive correlations at baseline. After adjusting for several clinical factors, both urinary CCR and NAPCR had significant associations with the decline of the estimated glomerular filtration rate (eGFR) (r = 0.160, P = 0.021; r = 0.412, P &amp;lt; 0.001, respectively). Urinary CCR had positive correlations with the decline of eGFR in the subpopulation of patients with eGFR ≥60 mL/min/1.73 m2. In patients with eGFR ≥60 mL/min/1.73 m2 and normoalbuminuria, only urinary NAPCR showed a significant association with the decline of eGFR; urinary CCR did not. In multivariate regression analysis, the number of patients who progressed to chronic kidney disease stage 3 or greater was higher in those in the upper tertiles of both the urinary levels of cystatin C and NAP than in those in the lower tertiles. CONCLUSIONS The results of this study suggest that urinary cystatin C and NAP may be predictors of the progression of type 2 diabetic nephropathy.
Compliance with and accuracy of daily self-assessment of peak expiratory flows (PEF) in asthmatic subjects over a three month period
Authors: P Verschelden, A Cartier, J L'Archeveque, C Trudeau, JL Malo
Journal: European Respiratory Journal (1996)

Serial peak expiratory flow (PEF) assessment has been proposed in the clinical evaluation of asthma. In subjects attending the asthma clinic of a tertiary care hospital, we wanted to assess: 1) compliance in performing PEF; and 2) accuracy of a PEF-diary. Twenty adult asthmatic subjects, all using inhaled steroids, were asked to assess their PEF in the morning and evening with a VMX instrument (Clement Clarke Int., Colombus, OH, USA). This instrument, which incorporates a standard mini-Wright peak flow meter, stores PEF data on a computer chip. Subjects were not informed that the values were being stored. The mean duration of PEF monitoring was 89 days (range 44-131 days). For the total of 20 subjects, it was estimated that 3,482 values should have been written down and stored on the VMX computer chip. Whilst 1,897 values (54%) were written down, only 1,533 (44%) were stored, 425 values being invented. Morning and evening values were stored on 34% of days; and values were stored at least once a day on 55% of days. The values written down corresponded precisely to stored values 90% of the time, and were within +/- 20 L 94% of the time. We conclude that: 1) compliance with daily peak expiratory flow assessments is generally poor in chronic stable asthmatic subjects assessed on two visits separated by a 3 month period; and 2) a substantial percentage of values (22%) is invented. The unsatisfactory compliance with peak expiratory flow monitoring in this group of asthmatics on inhaled steroids underlines the need for similar studies on peak expiratory flow monitoring as part of an action treatment plan, and in more severe and brittle asthmatics.