tbuckley/cabot-search huggingface dataset:
Long-Term Analysis and Prospective Validation of a Prognostic Model for Patients with High-Risk Primary Breast Cancer Receiving High-Dose Chemotherapy
Authors: Yago Nieto, Samia Nawaz, Elizabeth J. Shpall, Scott I. Bearman, James Murphy, Roy B. Jones
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We described previously a prognostic model for high-risk primary breast cancer patients receiving high-dose chemotherapy (HDC). Such model included nodal ratio (no. involved nodes:no. dissected nodes), tumor size, hormone receptors, and HER2. In the present study we intended to test this model prospectively in a second patient cohort. In addition, we analyzed the long-term overall outcome of our HDC trials. Experimental Design: We analyzed all 264 patients enrolled since 1990 in our prospective trials for 4–9+, ≥10+ nodes, or inflammatory disease. Patients of the second cohort (treated since 1997) had their prognostic score estimated prospectively before receiving HDC. Results: Fourteen patients (5.3%) died from HDC-related complications. At median follow-up of 7.1 years, relapse-free survival and overall survival of the whole group were 69.8% and 73%, respectively. Median time to relapse was 14 months (63.5% relapses within the first 2 years, 6.7% after year 5). The model was validated in the second cohort, establishing the following pretransplant risk categories: low risk (low score, HER2−), 44% patients, 87% freedom from relapse (FFR); intermediate risk (low score, HER2+), 29% patients, 68% FFR; and high risk (high score, any HER2), 27% patients, 49% FFR. Conclusions: Few relapses are seen after year 5 of follow-up, which indicates the need for mature results of the randomized trials before their final interpretation or meta-analysis. Our prospectively validated prognostic model, if additionally confirmed in the randomized trial populations, may provide an insight into the relative benefit of HDC in different risk patient subsets.
Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages
Authors: Kinga A. Powers, Katalin Szászi, Rachel G. Khadaroo, Patrick S. Tawadros, John C. Marshall, András Kapus, Ori D. Rotstein
Journal: The Journal of Experimental Medicine (2006)

Oxidative stress generated by ischemia/reperfusion is known to prime inflammatory cells for increased responsiveness to subsequent stimuli, such as lipopolysaccharide (LPS). The mechanism(s) underlying this effect remains poorly elucidated. These studies show that alveolar macrophages recovered from rodents subjected to hemorrhagic shock/resuscitation expressed increased surface levels of Toll-like receptor 4 (TLR4), an effect inhibited by adding the antioxidant N-acetylcysteine to the resuscitation fluid. Consistent with a role for oxidative stress in this effect, in vitro H2O2 treatment of RAW 264.7 macrophages similarly caused an increase in surface TLR4. The H2O2-induced increase in surface TLR4 was prevented by depleting intracellular calcium or disrupting the cytoskeleton, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy transfer between TLR4 and the raft marker GM1 as well as biochemical analysis of the raft components demonstrated that oxidative stress redistributes TLR4 to lipid rafts in the plasma membrane. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-β-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system.
Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation
Authors: F. Pietrantonio, F. Perrone, F. de Braud, A. Castano, C. Maggi, I. Bossi, A. Gevorgyan, P. Biondani, M. Pacifici, A. Busico, M. Gariboldi, F. Festinese, E. Tamborini, M. Di Bartolomeo
Journal: Annals of Oncology (2013)
Statin Use at the Time of Initiation of Androgen Deprivation Therapy and Time to Progression in Patients With Hormone-Sensitive Prostate Cancer
Authors: Lauren C. Harshman, Xiaodong Wang, Mari Nakabayashi, Wanling Xie, Loana Valenca, Lillian Werner, Yongjiang Yu, Aaron M. Kantoff, Christopher J. Sweeney, Lorelei A. Mucci, Mark Pomerantz, Gwo-Shu Mary Lee, Philip W. Kantoff
Journal: JAMA Oncology (2015)

Statin use has been associated with improved prostate cancer outcomes. Dehydroepiandrosterone sulfate (DHEAS) is a precursor of testosterone and a substrate for SLCO2B1, an organic anionic transporter. We previously demonstrated that genetic variants of SLCO2B1 correlated with time to progression (TTP) during receipt of androgen deprivation therapy (ADT). Statins also use SLCO2B1 to enter cells, and thus we hypothesized that they may compete with DHEAS uptake by the tumor cells.To evaluate whether statin use prolongs TTP during ADT for hormone-sensitive prostate cancer.In vitro studies were performed using prostate cancer cell lines at an academic, comprehensive cancer center. Statin use was retrospectively analyzed in 926 patients who had received ADT for biochemical or metastatic recurrence or de novo metastatic prostate cancer between January 1996 and November 2013.To determine whether statins interfere with DHEAS uptake, we performed in vitro studies using prostate cancer cell lines. Next, we queried our institutional clinical database to assess for an association between statin use and TTP during ADT using multivariable Cox regression analysis and adjusted for known prognostic factors.In vitro, we demonstrated that statins block DHEAS uptake by competitively binding to SLCO2B1. In our ADT cohort of 926 patients, 283 (31%) were taking a statin at ADT initiation. After a median follow-up of 5.8 years, 644 patients (70%) had experienced disease progression while receiving ADT. Median TTP during ADT was 20.3 months (95% CI, 18-24 months). Men taking statins had a longer median TTP during ADT compared with nonusers (27.5 [95% CI, 21.1-37.7] vs 17.4 [95% CI, 14.9-21.1] months; P < .001). The association remained statistically significant after adjusting for predefined prognostic factors (adjusted hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). The positive statin effect was observed for both patients with and without metastases (adjusted hazard ratio, 0.79 [95% CI, 0.58-1.07] for M0 disease and 0.84 [95% CI, 0.67-1.06] for M1 disease; P for interaction = .72).Statin use at the time of ADT initiation was associated with a significantly longer TTP during ADT even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce DHEAS uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged TTP in statin users.
Induction of Drug-Metabolizing Enzymes: A Path to the Discovery of Multiple Cytochromes P450
Authors: Allan H. Conney
Journal: The Annual Review of Pharmacology and Toxicology (2003)

This article provides a personal account of the discovery of the induced synthesis of drug-metabolizing enzymes and of subsequent research that led to the discovery of multiple cytochromes P450 with different catalytic activities. The manuscript also emphasizes the role of environmental factors (in addition to genetic polymorphisms) in explaining person-to-person and day-to-day differences in rates and pathways of drug metabolism that occur in the human population.
The Contributions of Breast Density and Common Genetic Variation to Breast Cancer Risk
Authors: Celine M. Vachon, V. Shane Pankratz, Christopher G. Scott, Lothar Haeberle, Elad Ziv, Matthew R. Jensen, Kathleen R. Brandt, Dana H. Whaley, Janet E. Olson, Katharina Heusinger, Carolin C. Hack, Sebastian M. Jud, Matthias W. Beckmann, Ruediger Schulz-Wendtland, Jeffrey A. Tice, Aaron D. Norman, Julie M. Cunningham, Kristen S. Purrington, Douglas F. Easton, Thomas A. Sellers, Karla Kerlikowske, Peter A. Fasching, Fergus J. Couch
Journal: JNCI Journal of the National Cancer Institute (2015)

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (Pinteraction = .23). Relative to those with scattered fibroglandular densities and average PRS (2nd quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.
Sex-Biased Dispersal and Volcanic Activities Shaped Phylogeographic Patterns of Extant Orangutans (genus: Pongo)
Authors: Alexander Nater, Pirmin Nietlisbach, Natasha Arora, Carel P. van Schaik, Maria A. van Noordwijk, Erik P. Willems, Ian Singleton, Serge A. Wich, Benoit Goossens, Kristin S. Warren, Ernst J. Verschoor, Dyah Perwitasari-Farajallah, Joko Pamungkas, Michael Krützen
Journal: Molecular Biology and Evolution (2011)

The Southeast Asian Sunda archipelago harbors a rich biodiversity with a substantial proportion of endemic species. The evolutionary history of these species has been drastically influenced by environmental forces, such as fluctuating sea levels, climatic changes, and severe volcanic activities. Orangutans (genus: Pongo), the only Asian great apes, are well suited to study the relative impact of these forces due to their well-documented behavioral ecology, strict habitat requirements, and exceptionally slow life history. We investigated the phylogeographic patterns and evolutionary history of orangutans in the light of the complex geological and climatic history of the Sunda archipelago. Our study is based on the most extensive genetic sampling to date, covering the entire range of extant orangutan populations. Using data from three mitochondrial DNA (mtDNA) genes from 112 wild orangutans, we show that Sumatran orangutans, Pongo abelii, are paraphyletic with respect to Bornean orangutans (P. pygmaeus), the only other currently recognized species within this genus. The deepest split in the mtDNA phylogeny of orangutans occurs across the Toba caldera in northern Sumatra and, not as expected, between both islands. Until the recent past, the Toba region has experienced extensive volcanic activity, which has shaped the current phylogeographic patterns. Like their Bornean counterparts, Sumatran orangutans exhibit a strong, yet previously undocumented structuring into four geographical clusters. However, with 3.50 Ma, the Sumatran haplotypes have a much older coalescence than their Bornean counterparts (178 kya). In sharp contrast to the mtDNA data, 18 Y-chromosomal polymorphisms show a much more recent coalescence within Sumatra compared with Borneo. Moreover, the deep geographic structure evident in mtDNA is not reflected in the male population history, strongly suggesting male-biased dispersal. We conclude that volcanic activities have played an important role in the evolutionary history of orangutans and potentially of many other forest-dwelling Sundaland species. Furthermore, we demonstrate that a strong sex bias in dispersal can lead to conflicting patterns in uniparentally inherited markers even at a genus-wide scale, highlighting the need for a combined usage of maternally and paternally inherited marker systems in phylogenetic studies.
Review focus on epigenetics and the histone code in vascular biology
Authors: S. Yla-Herttuala, C. K. Glass
Journal: Cardiovascular Research (2011)

A current search of the PubMed database for the term ‘epigenetic’ returns more than 18 000 papers. Strikingly, nearly half of these papers have appeared in the past 3 years, marking an explosion of research efforts on this topic. Equally striking is the range of biological processes that are encompassed by these papers, including fundamental aspects of development in diverse organisms and basic mechanisms of transcriptional control and DNA damage repair. As progress in understanding epigenetic mechanisms has advanced, the definition of ‘epigenetic’ for many molecular and cellular biologists has evolved from ‘a process that accounts for heritable changes in gene expression that are not associated with genomic mutations’ to ‘the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states’.1 This broader definition acknowledges common underlying molecular mechanisms that can alter chromatin states, e.g. through DNA methylation or histone modifications, some of which may be heritable through mitosis and/or meiosis and others that may be transient. Among the best-known examples of heritable epigenetic states are imprinting of some maternal genes, developmental effects like queen bee vs. soldier bee development based on the availability of food (royal jelly), and epigenetic alterations in several types of cancers.1 However, epigenetic mechanisms also play important roles in the regulation of many other physiological processes, such as gene expression patterns in different tissues, cell differentiation, and responses to various environmental stimuli. Epigenetics has been previously studied mostly in the cancer field and in developmental biology, but …
Arresting developments in the cardiac myocyte cell cycle: Role of cyclin-dependent kinase inhibitors
Authors: G Brooks
Journal: Cardiovascular Research (1998)

Like most other cells in the body, foetal and neonatal cardiac myocytes are able to divide and proliferate. However, the ability of these cells to undergo cell division decreases progressively during development such that adult myocytes are unable to divide. A major problem arising from this inability of adult cardiac myocytes to proliferate is that the mature heart is unable to regenerate new myocardial tissue following severe injury, e.g. infarction, which can lead to compromised cardiac pump function and even death. Studies in proliferating cells have identified a group of genes and proteins that controls cell division. These proteins include cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs), which interact with each other to form complexes that are essential for controlling normal cell cycle progression. A variety of other proteins, e.g. the retinoblastoma protein (pRb) and members of the E2F family of transcription factors, also can interact with, and modulate the activities of, these complexes. Despite the major role that these proteins play in other cell types, little was known until recently about their existence and activities in immature (proliferating) or mature (non-proliferating) cardiac myocytes. The reason(s) why cardiac myocytes lose their ability to divide during development remains unknown, but if strategies were developed to understand the mechanisms underlying cardiac myocyte growth, it could open up new avenues for the treatment of cardiovascular disease. In this article, we shall review the function of the cell cycle machinery and outline some of our recent findings pertaining to the involvement of the cell cycle in modulating cardiac myocyte growth and hypertrophy.
PRACTICAL ASPECTS OF MESANTOIN THERAPY IN EPILEPSY
Authors: JOSEPH L. FETTERMAN, VICTOR M. VICTOROFF
Journal: American Journal of Psychiatry (1948)

1. Two years' experience with Mesantoin shows it to be a highly valuable anticonvulsant drug. It can be used alone in the control of grand mal, especially Jacksonian attacks. It may be of some benefit in psychomotor seizures. 2. We have found that Mesantoin is best combined with dilantin sodium. Dilantin sodium is still perhaps the most effective anticonvulsant remedy and should be the base upon which other drugs are added. 3. The dosage of Mesantoin and dilantin sodium must be individualized and adjusted to the need of the patient. May we impress the goal of a limited number of spells, not a reduced number of pills. 4. A common effective dose for adults is dilantin sodium 1 to 3 capsules, and mesantoin, 4 to 6 tablets daily. This combination has proved more effective in controlling seizures than any previous single drug or combined drugs which we have used. 5. Side actions of Mesantoin include drowsiness and skin rash. As a rule patients acquire tolerance to the drowsiness in a period of time. Dexedrine and physical activity tend to free the patients from the somnolence. 6. Effective control of an epileptic requires close and continued observation and treatment.
The association between cardiorespiratory fitness and C-reactive protein in subjects with the metabolic syndrome
Authors: Doron Aronson, Ron Sella, Muhammad Sheikh-Ahmad, Arthur Kerner, Ophir Avizohar, Shmuel Rispler, Peter Bartha, Walter Markiewicz, Yishai Levy, Gerald J. Brook
Journal: Journal of the American College of Cardiology (2004)
TRANCE Is Necessary and Sufficient for Osteoblast-mediated Activation of Bone Resorption in Osteoclasts
Authors: Karen Fuller, Brian Wong, Simon Fox, Yongwon Choi, Tim J. Chambers
Journal: The Journal of Experimental Medicine (1998)

TRANCE (tumor necrosis factor–related activation-induced cytokine) is a recently described member of the tumor necrosis factor superfamily that stimulates dendritic cell survival and has also been found to induce osteoclastic differentiation from hemopoietic precursors. However, its effects on mature osteoclasts have not been defined. It has long been recognized that stimulation of osteoclasts by agents such as parathyroid hormone (PTH) occurs through a hormonal interaction with osteoblastic cells, which are thereby induced to activate osteoclasts. To determine whether TRANCE accounts for this activity, we tested its effects on mature osteoclasts. TRANCE rapidly induced a dramatic change in osteoclast motility and spreading and inhibited apoptosis. In populations of osteoclasts that were unresponsive to PTH, TRANCE caused activation of bone resorption equivalent to that induced by PTH in the presence of osteoblastic cells. Moreover, osteoblast-mediated stimulation of bone resorption was abrogated by soluble TRANCE receptor and by the soluble decoy receptor osteoprotegerin (OPG), and stimulation of isolated osteoclasts by TRANCE was neutralized by OPG. Thus, TRANCE expression by osteoblasts appears to be both necessary and sufficient for hormone-mediated activation of mature osteoclasts, and TRANCE-R is likely to be a receptor for signal transduction for activation of the osteoclast and its survival.
KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions
Authors: David E. White, Dmitri Negorev, Hongzhuang Peng, Alexey V. Ivanov, Gerd G. Maul, Frank J. Rauscher
Journal: Cancer Research (2006)

The DNA damage response requires a coordinated nucleo-cytoplasmic cascade of events, which ultimately converge on damaged DNA packaged in chromatin. Few connections between the proteins that remodel chromatin and the proteins that mediate this damage response have been shown. We have investigated the DNA damage-induced phosphorylation of the KRAB-ZFP-associated protein 1 (KAP1), the dedicated corepressor for Krüppel-associated box (KRAB) zinc finger protein (ZFP) proteins. We show that KAP1 is rapidly phosphorylated following DNA damage by members of the phosphatidylinositol-3 kinase-like family of kinases. This phosphorylation occurs at a single amino acid residue that is conserved from mice to humans and is located adjacent to the bromodomain, suggesting that it may regulate chromatin recognition by that module. Phosphorylated KAP1 rapidly localizes to sites of DNA strand breaks in the nucleus in response to ionizing radiation. This discovery provides a novel link between chromatin-mediated transcriptional repression and the recognition/repair of DNA, which must be accomplished by the cellular DNA damage response.
A cost-utility analysis of pimecrolimus vs. topical corticosteroids and emollients for the treatment of mild and moderate atopic eczema
Authors: M. Pitt, R. Garside, K. Stein
Journal: British Journal of Dermatology (2006)

Conventional treatments for atopic eczema include topical corticosteroids (TCS) and emollients. Pimecrolimus, an immunosuppressant, was licensed in the U.K. in 2003 as an alternative treatment of mild to moderate atopic eczema.To assess the cost-utility of pimecrolimus as a treatment for mild and moderate atopic eczema when compared with conventional treatments which use TCS and emollients.A Markov state-transition model was developed to represent the cyclical nature of atopic eczema and provide an economic analysis of cost-utility for treatment alternatives from the perspective of a third party payer (U.K. National Health Service). A range of methods was used to obtain data for transition probabilities, costs and quality of life. These included a systematic review of published effectiveness data, expert opinion, and a utility study conducted by the authors. Separate cohort analyses were modelled to distinguish between children and adult populations and between differing treatment patterns for facial and body eczema. One-way sensitivity analyses and probabilistic sensitivity analysis (using Monte-Carlo simulation) were performed.Baseline cost-utility outputs from the model show that, in all tested scenarios, TCS dominate pimecrolimus (i.e. TCS are both cheaper and more effective). However, the differences in benefits between treatments output by the model are very small. Sensitivity analyses highlight the importance of cost variations in pimecrolimus. Where pimecrolimus is compared with emollient only it is probably cost effective at a willingness-to-pay threshold of 30 000 UK pounds per quality-adjusted life year.There are likely to be few situations in which the use of pimecrolimus for the treatment of atopic eczema can be justified on economic grounds. Exceptions are likely to be in cases where TCS have been shown to be ineffective, unacceptable due to adverse events, or where a patient is unwilling to accept TCS treatment despite appropriate education and support and emollient alone is the alternative clinical option.
Biological activity of anastrozole in postmenopausal patients with advanced breast cancer: effects on estrogens and bone metabolism
Authors: E. Bajetta, A. Martinetti, N. Zilembo, P. Pozzi, I. La Torre, L. Ferrari, E. Seregni, R. Longarini, G. Salvucci, E. Bombardieri
Journal: Annals of Oncology (2002)