tbuckley/cabot-search huggingface dataset:
Sulfation and glucuronidation as competing pathways in the metabolism of hydroxamic acids: the role of N,O-sulfonation in chemical carcinogenesis of aromatic amines.
Authors: G J Mulder, J H Meerman
Journal: Environmental Health Perspectives (1983)

Aromatic amines can be metabolized by N-acetylation and N-hydroxylation to hydroxamic acids; these subsequently are conjugated to form the N,O-sulfonate and N,O-glucuronide conjugates. The N,O-sulfonates are highly labile metabolites that generate reactive intermediates involved in the covalent binding of the parent compound to protein, RNA and DNA, as well as to low molecular compounds like glutathione. This paper discusses methods used to decrease sulfation in vivo, and thereby to enhance the formation of the more stable N,O-glucuronides from N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylamino-4'-fluorobiphenyl. Acetaminophen pretreatment decreases the sulfate availability, but results in many side effects that complicate the analysis of the results. An 8% casein diet reduces the sulfate availability in the rat to approximately 20% of control and thus offers an effective approach to decrease sulfation. The most effective selective inhibition of sulfation is by pentachlorophenol, which very strongly reduces N,O-sulfonation of both hydroxamic acids, and selectively inhibits the formation of DNA adducts that have retained the N-acetyl group. This inhibitor and the related 2,6-dichloro-4-nitrophenol can be employed to study the role of sulfation of hydroxamic acids in initiation and promotion of tumor formation by aromatic amines.
Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas
Authors: Saskia M. Wilting, Renske D.M. Steenbergen, Marianne Tijssen, Wessel N. van Wieringen, Theo J.M. Helmerhorst, Folkert J. van Kemenade, Maaike C.G. Bleeker, Mark A. van de Wiel, Beatriz Carvalho, Gerrit A. Meijer, Bauke Ylstra, Chris J.L.M. Meijer, Peter J.F. Snijders
Journal: Cancer Research (2009)

Cervical cancer develops from precancerous high-grade cervical intraepithelial neoplasia (CIN) harboring a transforming infection with high-risk human papillomavirus, which is characterized by p16(INK4a) overexpression. Once such a lesion has developed, progression toward an invasive squamous cell carcinoma (SCC) may take one or more decades, underlining the heterogeneity of these lesions in terms of duration of existence and progression risk. We performed array-based comparative genomic hybridization (array CGH) on 46 p16(INK4a) immunopositive CIN2/3 lesions to determine whether this heterogeneity is reflected in their chromosomal profiles. Chromosomal profiles of CIN2/3 lesions were related to those of invasive cervical SCC and promoter methylation of CADM1, a tumor suppressor gene known to be functionally involved in the tumorigenic phenotype of cervical cancer cells. Frequent alterations found in CIN2/3 lesions included gains located at chromosome 1, 3, 7, and 20 and losses located at 4, 11, 16, 17, and 19. Unsupervised hierarchical clustering identified two subsets of CIN2/3 lesions, chromosomal profiles of one of which closely resembled invasive SCCs. Gains of 1, 3q, and 20 were characteristic for CIN2/3 lesions with chromosomal signatures resembling carcinomas. In addition, dense promoter methylation of the CADM1 gene was significantly more frequent in these CIN2/3 lesions (P = 0.004). No chromosomal alterations were detected in six CIN1 lesions, five of which were completely p16(INK4a) immunonegative. These findings suggest that biomarkers associated with gains at chromosomes 1, 3q, and 20 are potential hallmarks of advanced p16(INK4a)-positive CIN2/3 lesions with a high short-term risk of progression.
Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL
Authors: Matthew C. Stubbs, Wonil Kim, Megan Bariteau, Tina Davis, Sridhar Vempati, Janna Minehart, Matthew Witkin, Jun Qi, Andrei V. Krivtsov, James E. Bradner, Andrew L. Kung, Scott A. Armstrong
Journal: Clinical Cancer Research (2015)

Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms.A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity. Isoform-specific shRNAs were used as further validation of HDACs as relevant therapeutic targets in B-ALL. Mouse xenografts of B-cell malignancy-derived cell lines and a pediatric B-ALL were used to demonstrate pharmacologic efficacy.Nonselective HDAC inhibitors were cytotoxic to a panel of B-ALL cell lines as well as to xenografted human leukemia patient samples. Assessment of isoform-specific HDACi indicated that targeting HDAC1-3 with class I HDAC-specific inhibitors was sufficient to inhibit growth of B-ALL cell lines. Furthermore, shRNA-mediated knockdown of HDAC1 or HDAC2 resulted in growth inhibition in these cells. We then assessed a compound that specifically inhibits only HDAC1 and HDAC2. This compound suppressed growth and induced apoptosis in B-ALL cell lines in vitro and in vivo, whereas it was far less effective against other B-cell-derived malignancies.Here, we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL.
Understanding the Lethal Variant of Prostate Cancer: Power of Examining Extremes
Authors: Ana Aparicio, Christopher J. Logothetis, Sankar N. Maity
Journal: Cancer Discovery (2011)

Abstract Small cell prostate carcinoma is a lethal variant of castration-resistant prostate cancer. Beltran and colleagues identified overexpression and amplification of both aurora kinase A (AURKA) and the MYCN proto-oncogene in the small cell prostate carcinomas and propose Aurora kinase A as a potential therapeutic target in this disease subset. Cancer Discovery; 1(6); 466–68. ©2011 AACR. Commentary on Beltran et al., p. 487.
Risk of Cardiovascular Disease by Hysterectomy Status, With and Without Oophorectomy
Authors: Barbara V. Howard, Lewis Kuller, Robert Langer, JoAnn E. Manson, Catherine Allen, Annlouise Assaf, Barbara B. Cochrane, Joseph C. Larson, Norman Lasser, Monique Rainford, Linda Van Horn, Marcia L. Stefanick, Maurizio Trevisan
Journal: Circulation (2005)

Background— Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in women and may vary by hysterectomy (or oophorectomy) status. This study compared CVD risk factors and rates between postmenopausal women who had and had not undergone hysterectomy, with or without oophorectomy. Methods and Results— This analysis was conducted on 89 914 women in the Women’s Health Initiative (WHI) Observational Study. Participants reported demographic characteristics, medical history, dietary habits, physical activity, medications, and previous hysterectomy (with or without oophorectomy). Baseline weight, height, waist circumference, and blood pressure were measured. CVD events were ascertained during 5.1 years of mean follow-up and adjudicated with standard criteria. Black, Hispanic, and American Indian women had higher rates of hysterectomy than white women (52.9%, 44.6%, and 49.2% versus 40.0%, respectively), and Asian/Pacific Islander women had lower rates (33.8%). Women with a hysterectomy (regardless of oophorectomy status) had an adverse risk profile at baseline compared with women with no hysterectomy, including a higher proportion of hypertension, diabetes, high cholesterol, obesity, and lower education, income, and physical activity (all P &lt;0.01). Total mortality and fatal and nonfatal CVD were higher among women with a hysterectomy. Hysterectomy (regardless of oophorectomy status) was a significant predictor of CVD (HR: 1.26, P &lt;0.001). After adjustment for demographic variables and CVD risk factors, the effect was reduced and nonsignificant. Conclusions— Women with a hysterectomy had a worse risk profile and higher prevalence and incidence of CVD in this cohort. Multivariate models suggest that hysterectomy is not the major determinant of this outcome; rather, CVD risk may be due to the more adverse initial risk profile of women who had undergone hysterectomy.
THE TOXICOLOGY OF ENVIRONMENTAL TOBACCO SMOKE
Authors: Hanspeter Witschi, Jesse P. Joad, Kent E. Pinkerton
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract It has by now become obvious that environmental tobacco smoke (ETS) may pose a health risk to nonsmokers. Epidemiological data suggest that exposure to ETS may increase the risk of developing lung cancer, cardiovascular disease, intrauterine growth retardation, predisposition to chronic lung disease, and sudden infant death syndrome. The human populations most at risk from ETS exposure appear to be neonates, young children, and possibly the fetus while in utero. Experimental studies with cigarette sidestream smoke (SS) have successfully duplicated several of these disease conditions in laboratory animals, particularly the effects of SS on fetal growth, lung maturation, and altered airway reactivity. The availability of animal models may open the way to fruitful experimental studies on mechanisms that help us to better understand disease.
Protective Effects of Silymarin Against Photocarcinogenesis in a Mouse Skin Model
Authors: S. K. Katiyar, N. J. Korman, H. Mukhtar, R. Agarwal
Journal: JNCI Journal of the National Cancer Institute (1997)

Nonmelanoma skin cancer is the most common cancer among humans; solar UV is its major cause. Therefore, it is important to identify agents that can offer protection against this cancer.We evaluated the protective effects of silymarin, a flavonoid compound isolated from the milk thistle plant, against UVB radiation-induced nonmelanoma skin cancer in mice and delineated the mechanism(s) of its action.For long-term studies, three different protocols of treatment were employed, each evaluating protection by silymarin at a different stage of carcinogenesis. Female SKH-1 hairless mice were subjected to 1) UVB-induced tumor initiation followed by phorbol ester-mediated tumor promotion, 2) 7,12-dimethylbenz[a]anthracene-induced tumor initiation followed by UVB-mediated tumor promotion, and 3) UVB-induced complete carcinogenesis. Forty mice were used in each protocol and were divided into control and treatment groups. Silymarin was applied topically at a dose of 9 mg per application before UVB exposure, and its effects on tumor incidence (% of mice with tumors), tumor multiplicity (number of tumors per mouse), and average tumor volume per mouse were evaluated. In short-term studies, the following parameters were measured: formation of sunburn and apoptotic cells, skin edema, epidermal catalase and cyclooxygenase (COX) activities, and enzymatic activity and messenger RNA (mRNA) expression for ornithine decarboxylase (ODC), a frequently observed marker at tumor promotion stage. Fisher's exact test was used to evaluate differences in tumor incidence, two-sample Wilcoxon rank sum test was used for tumor multiplicity and tumor volume, and Student's t test was used for all other measurements. All statistical tests were two-sided.In the protocol with UVB-induced tumor initiation, silymarin treatment reduced tumor incidence from 40% to 20% (P = .30), tumor multiplicity by 67% (P = .10), and tumor volume per mouse by 66% (P = .14). In the protocol with UVB-induced tumor promotion, silymarin treatment reduced tumor incidence from 100% to 60% (P<.003), tumor multiplicity by 78% (P<.0001), and tumor volume per mouse by 90% (P<.003). The effect of silymarin was much more profound in the protocol with UVB-induced complete carcinogenesis, where tumor incidence was reduced from 100% to 25% (P<.0001), tumor multiplicity by 92% (P<.0001), and tumor volume per mouse by 97% (P<.0001). In short-term experiments, silymarin application resulted in statistically significant inhibition in UVB-caused sunburn and apoptotic cell formation, skin edema, depletion of catalase activity, and induction of COX and ODC activities and ODC mRNA expression.Silymarin can provide substantial protection against different stages of UVB-induced carcinogenesis, possibly via its strong antioxidant properties. Clinical testing of its usefulness is warranted.
New Target, New Drug, Old Paradigm
Authors: Manuel Hidalgo
Journal: Journal of Clinical Oncology (2004)

The last few years have witnessed the clinical development of many novel, so-called targeted anticancer agents. The clinical development of most of these drugs has been guided by traditional clinical research methods. With these approaches, some of these drugs have progressed from phase I to phase III trials, and fewer have eventually received regulatory approval based on evidence—sometimes rather limited— of patient benefit. Although these examples can be viewed as great successes, as indeed are any interventions that significantly decrease cancer suffering, their success does not mean that the clinical trial approaches used are optimal. In general, these processes are very slow and costly. Early dose-finding studies are still based on toxicity, despite many of the new agents’ failure to exert linear dosedependent toxicity effects. As a consequence, multiple different doses and schedules are explored in phase I and II studies, significantly complicating the design and conduct of large-scale, randomized trials. In many instances, the “go or no-go” decision is based on response rates, when these drugs in the laboratory induce growth arrest rather than tumor shrinkage. In addition, the interpretation of the biologic bases of the antitumor effects of these drugs has been superficial, leading to large developmental efforts in the wrong diseases. This is perhaps best exemplified by the development of the farnesyl transferase inhibitors designed to inhibit Ras signaling in patients with pancreatic cancer, on the basis that these tumors frequently have mutations in the ras gene. 1 Importantly, no effort has been made to learn the biologic basis for success or failure, and the goal remains unselected patient populations, based on weak and arbitrary criteria, rather than the individual. In this issue of the Journal of Clinical Oncology is the first phase I clinical trial of CCI-779, an inhibitor of the mammalian target of rapamycin (mTOR) and a novel drug with a novel mechanism of action. 2 This trial is a good example of the limitations of the traditional methodology of phase I clinical studies in the development of targeted agents. mTOR is a serine/threonine kinase (a member of the phosphatidyl inositol-3 (PI3K)–related kinases) that plays a pivotal regulatory role in multiple cellular functions, such as the transduction of proliferative signals by growth factors and the response of cells to nutrients. mTOR was discovered in part because of the existence of rapamycin, a naturally occurring inhibitor of mTOR. Rapamycin has been known for years to have unique biologic properties, including immunosuppressive, antifungal, and antiproliferative effects. Based on these features, rapamycin-like drugs have been developed as anticancer agents. 3-5 In preclinical models, mTOR inhibitors exert tumor growth inhibition, induce apoptosis in selected models, and inhibit angiogenesis. 6 CCI-779 is an ester of rapamycin selected for clinical development.
Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivoin tumor xenografts and human breast tumors
Authors: Chad J Creighton, Kevin E Cordero, Jose M Larios, Rebecca S Miller, Michael D Johnson, Arul M Chinnaiyan, Marc E Lippman, James M Rae
Journal: Genome biology (2006)

Estrogen plays a central role in breast cancer pathogenesis. Although many studies have characterized the estrogen regulation of genes using in vitro cell culture models by global mRNA expression profiling, it is not clear whether these genes are similarly regulated in vivo or how they might be coordinately expressed in primary human tumors.We generated DNA microarray-based gene expression profiles from three estrogen receptor alpha (ERalpha)-positive breast cancer cell lines stimulated by 17beta-estradiol (E2) in vitro over a time course, as well as from MCF-7 cells grown as xenografts in ovariectomized athymic nude mice with E2 supplementation and after its withdrawal. When the patterns of genes regulated by E2 in vitro were compared to those obtained from xenografts, we found a remarkable overlap (over 40%) of genes regulated by E2 in both contexts. These patterns were compared to those obtained from published clinical data sets. We show that, as a group, E2-regulated genes from our preclinical models were co-expressed with ERalpha in a panel of ERalpha+ breast tumor mRNA profiles, when corrections were made for patient age, as well as with progesterone receptor. Furthermore, the E2-regulated genes were significantly enriched for transcriptional targets of the myc oncogene and were found to be coordinately expressed with Myc in human tumors.Our results provide significant validation of a widely used in vitro model of estrogen signaling as being pathologically relevant to breast cancers in vivo.
Safety of Herpes Zoster Vaccine in the Shingles Prevention Study
Authors: Michael S. Simberkoff, Robert D. Arbeit, Gary R. Johnson, Michael N. Oxman, Kathy D. Boardman, Heather M. Williams, Myron J. Levin, Kenneth E. Schmader, Lawrence D. Gelb, Susan Keay, Kathleen Neuzil, Richard N. Greenberg, Marie R. Griffin, Larry E. Davis, Vicki A Morrison, Paula W. Annunziato
Journal: Annals of Internal Medicine (2010)

Background: The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. Objective: To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults. Design: Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501) Setting: 22 U.S. academic centers. Participants: 38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. Intervention: Single dose of herpes zoster vaccine or placebo. Measurements: Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. Results: After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. Limitations: Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. Conclusion: Herpes zoster vaccine is well tolerated in older, immunocompetent adults. Primary Funding Source: Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research.
Uses and Abuses of Concepts in Psychiatry
Authors: ERIK STRÖMGREN
Journal: American Journal of Psychiatry (1969)

Although the vocabulary of psychiatry does not exceed that of many other disciplines in size, it is unusually fluid, changing rapidly from time to time and from place to place. Psychiatrists have thus been accused at times of overindulgence in terms and concepts. This author examines the ways in which some terms and concepts have come into usage, the functions they serve, and the ways in which they have influenced development in the field. He concludes that Adolf Meyer's "critical pragmatism" remains the most useful approach to the problem of conceptualization and classification in psychiatry.
Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children
Authors: Ann E. Woolfrey, Claudio Anasetti, Barry Storer, Kristine Doney, Laurie A. Milner, Eric L. Sievers, Paul Carpenter, Paul Martin, Effie Petersdorf, Frederick R. Appelbaum, John A. Hansen, Jean E. Sanders
Journal: Blood (2002)
Plasma 25-Hydroxyvitamin D3 and Bladder Cancer Risk According to Tumor Stage and FGFR3 Status: A Mechanism-Based Epidemiological Study
Authors: André FS Amaral, Marinela Méndez-Pertuz, Alberto Muñoz, Debra T. Silverman, Yves Allory, Manolis Kogevinas, Josep Lloreta, Nathaniel Rothman, Alfredo Carrato, Manuel Rivas del Fresno, Francisco X. Real, Núria Malats
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundPrevious evidence suggests that 25-hydroxyvitamin D3 [25(OH)D3] protects against several cancers. However, little is known regarding urothelial bladder cancer (UBC). We analyzed the association between plasma 25(OH)D3 and overall risk of UBC, as well as according to stage and FGFR3 molecular subphenotypes.
Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators
Authors: Laura S. Angelo, Razelle Kurzrock
Journal: Clinical Cancer Research (2007)

Abstract Inflammation occurs in response to host injury or infection, as the result of an autoimmune disease, or in response to the development of a tumor. Although the immune system may be helpful in fighting the tumor, it may also fuel the tumorigenic process. In fact, recent data suggest a strong link between chronic inflammation, angiogenesis, and the development of cancer. For example, inflammation and scarring caused by recurring infections with Mycobacterium tuberculosis may be a cause for cancers of the lung. Inflammatory breast cancer exhibits increased angiogenesis and lymphangiogenesis and has a higher metastatic potential than noninflammatory breast cancer. Nonsteroidal anti-inflammatory drugs have been proposed as preventives for the development of colon carcinoma and ovarian cancer. Inhibition of nuclear factor-κB contributes to the proposed mechanism of action. Inflammatory cytokines, including interleukin-6, serve as autocrine and paracrine growth factors for several cancers, and high levels of these cytokines may correlate with a poor prognosis and increased production of angiogenic factors. The state of the art of our understanding of this critical interaction is reviewed.
Cardiovascular comorbidities in patients with rosacea: A nationwide case-control study from Taiwan
Authors: Tuan-Chun Hua, Pei-I Chung, Yi-Ju Chen, Lung-Chi Wu, Yen-Da Chen, Chian-Yaw Hwang, Szu-Yin Chu, Chih-Chiang Chen, Ding-Dar Lee, Yun-Ting Chang, Han-Nan Liu
Journal: Journal of the American Academy of Dermatology (2015)
Treatment of HBeAg (−) chronic hepatitis B with lamivudine vs. lamivudine+interferon: a randomized controlled clinical trial
Authors: C. Yurdaydin, H. Bozkaya, H. Çetinkaya, N. Sasmaz, T. Sahin, H. Altin, D. Oguz, A.R. Turkyilmaz, Ö. Erkan, A.M. Bozdayi, Ö. Uzunalimoglu
Journal: Journal of Hepatology (2001)