tbuckley/cabot-search huggingface dataset:
The potential benefits of low-molecular-weight heparins in cancer patients
Authors: Francisco Robert
Journal: Journal of Hematology & Oncology (2010)

Cancer patients are at increased risk of venous thromboembolism due to a range of factors directly related to their disease and its treatment. Given the high incidence of post-surgical venous thromboembolism in cancer patients and the poor outcomes associated with its development, thromboprophylaxis is warranted. A number of evidence-based guidelines delineate anticoagulation regimens for venous thromboembolism treatment, primary and secondary prophylaxis, and long-term anticoagulation in cancer patients. However, many give equal weight to several different drugs and do not make specific recommendations regarding duration of therapy. In terms of their efficacy and safety profiles, practicality of use, and cost-effectiveness the low-molecular-weight heparins are at least comparable to, and offer several advantages over, other available antithrombotics in cancer patients. In addition, data are emerging that the antithrombotics, and particularly low-molecular-weight heparins, may exert an antitumor effect which could contribute to improved survival in cancer patients when given for long-term prophylaxis. Such findings reinforce the importance of thromboprophylaxis with low-molecular-weight heparin in cancer patients.
Relating tissue specialization to the differentiation of expression of singleton and duplicate mouse proteins.
Authors: Shiri Freilich, Tim Massingham, Eric Blanc, Leon Goldovsky, Janet M Thornton
Journal: Genome biology (2006)

Abstract Background Gene duplications have been hypothesized to be a major factor in enabling the evolution of tissue differentiation. Analyses of the expression profiles of duplicate genes in mammalian tissues have indicated that, with time, the expression patterns of duplicate genes diverge and become more tissue specific. We explored the relationship between duplication events, the time at which they took place, and both the expression breadth of the duplicated genes and the cumulative expression breadth of the gene family to which they belong. Results We show that only duplicates that arose through post-multicellularity duplication events show a tendency to become more specifically expressed, whereas such a tendency is not observed for duplicates that arose in a unicellular ancestor. Unlike the narrow expression profile of the duplicated genes, the overall expression of gene families tends to maintain a global expression pattern. Conclusion The work presented here supports the view suggested by the subfunctionalization model, namely that expression divergence in different tissues, following gene duplication, promotes the retention of a gene in the genome of multicellular species. The global expression profile of the gene families suggests division of expression between family members, whose expression becomes specialized. Because specialization of expression is coupled with an increased rate of sequence divergence, it can facilitate the evolution of new, tissue-specific functions.
Abstract 5450:CYP2A6andERCC1polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients
Authors: Sook Ryun Park, Sun-Young Kong, Byung-Ho Nam, Il Ju Choi, Chan Gyoo Kim, Jong Yeul Lee, Soo-Jeong Cho, Young-Woo Kim, Keun Won Ryu, Jun Ho Lee, Jiyoung Rhee, Young-Iee Park, Noe Kyeong Kim
Journal: Cancer Research (2011)

Abstract Introduction: S-1 contains tegafur, which is converted to 5-fluorouracil by CYP2A6. We evaluated the association between polymorphisms of CYP2A6, ERCC1 and XRCC1 and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. Methods: Among chemonaive MGC patients (n=108) who received S-1 40 mg/m2 b.i.d. on days 1-14 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle, we analyzed the wild-type allele [W] (CYP2A6*1), four CYP2A6 variants [V] that abolish (CYP2A6*4) or reduce (CYP2A6*7, *9, *10) enzyme activity, and the polymorphisms of ERCC1 [8525C&amp;gt;T (rs11615), 19442C&amp;gt;A (rs3212986)] and XRCC1 [1196G&amp;gt;A (rs25487)]. Results: Patients having fewer CYP2A6 variants had significantly better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4 = 66.7% vs 58.3% vs 32.3%; P=0.008), time to progression (TTP) (median, 7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (median, 23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C&amp;gt;A was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (median, 4.4 vs 7.6 vs 7.9 months) (P=0.012). When we classified patients according to the number of risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C&amp;gt;A (C/C), patients carrying two vs those carrying none showed an adjusted odds ratio of 0.113 (95% CI, 0.025-0.509) (P=0.004) for response and adjusted hazard ratios of 3.748 (95% CI, 1.900-7.393) (P=0.0001) for TTP and 2.961 (95% CI, 1.371-6.393) (P=0.006) for death.Conclusion: CYP2A6 and ERCC1 19442C&amp;gt;A polymorphisms are important predictors for the efficacy of S-1/cisplatin in MGC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2011-5450
Evidence of Safety and Effectiveness for a Drug-Eluting Stent
Authors: Donald E. Cutlip
Journal: Circulation (2012)

D rug-eluting stents (DES) were introduced to the coro- nary artery disease treatment market in 2003 with much exuberance and fanfare.With Ͼ70% reduction in restenosis and no apparent safety concerns in 1-year reports from large randomized clinical trials, 1,2 the opportunity for expansion of the technology seemed limitless.Interventional cardiologists responded with confidence and quickly expanded use to a wide array of off-label indications, limited only by initial inventory constraints. 3,4Some even considered DES as a potential therapy for vulnerable lesions or regions that were not yet hemodynamically significant, and there were concerns by hospitals and others that widespread use of these devices for treatment of traditional surgical disease would place cardiac surgery programs in jeopardy. 5,6The realization of an increased risk of late and very late stent thrombosis with the first-generation DES, especially in patients with increased lesion complexity, dampened this enthusiasm. 7,
Side-effects of fluticasone in asthmatic children: no effects after dose reduction
Authors: M.J. Visser, E. van der Veer, D.S. Postma, L.R. Arends, T.W. de Vries, P.L.P. Brand, E.J. Duiverman
Journal: European Respiratory Journal (2004)

To assess long-term effects and side-effects of fluticasone propionate (FP), a 2-yr study was performed, comparing a step-down dose approach (1,000 µg·day −1 , with reductions every 2 months to 500, 200 and 100 µg·day −1 for the remainder of the study) versus a constant dose (200 µg·day −1 ). In 55 children with chronic persistent asthma, aged 6–10 yrs, airways hyperresponsiveness (AHR) and systemic side-effects (height, bone parameters and adrenal cortical function) were assessed at predetermined intervals in a double-blind prospective 2-yr study. AHR improved after 4 months treatment with 1,000 µg·day −1 FP followed by 500 µg·day −1 , without significant differences during long-term treatment between the two approaches. Dose-dependent reduction of growth velocity, adrenal cortical function and biochemical bone turnover was found during therapy with 1,000 and 500 µg·day −1 FP when compared with 200 µg·day −1 . In conclusion, doses of 1,000 and 500 µg·day −1 fluticasone propionate are associated with marked reductions of growth velocity, bone turnover and adrenal cortical function. However, conventional doses (≤200 µg·day −1 fluticasone propionate) appear to be safe in the long-term management of childhood asthma. From a safety point of view, high doses of fluticasone propionate should only be prescribed in exceptions, e.g. in persistent severe asthma.
Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors
Authors: Ignacio Duran, Sebastien J. Hotté, Holger Hirte, Eric X. Chen, Martha MacLean, Sandra Turner, Lixia Duan, Gregory R. Pond, Chetan Lathia, Scott Walsh, John J. Wright, Janet Dancey, Lillian L. Siu
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil
Authors: Laura G. M. Daenen, Geert A. Cirkel, Julia M. Houthuijzen, Johan Gerrits, Ilse Oosterom, Jeanine M. L. Roodhart, Harm van Tinteren, Kenji Ishihara, Alwin D. R. Huitema, Nanda M. Verhoeven-Duif, Emile E. Voest
Journal: JAMA Oncology (2015)

Our research group previously identified specific endogenous platinum-induced fatty acids (PIFAs) that, in picomolar quantities, activate splenic macrophages leading to resistance to chemotherapy in mouse models. Fish oil was shown to contain the PIFA 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) and when administered to mice neutralized chemotherapy activity.Because patients with cancer frequently use fish oil supplements, we set out to determine exposure to 16:4(n-3) after intake of fish or fish oil.(1) In November 2011, 400 patients with cancer undergoing treatment at the University Medical Center Utrecht were surveyed to determine their use of fish oil supplements; 118 patients responded to the questionnaire (30%); (2) pharmacokinetic analysis of the 16:4(n-3) content of 6 fish oils and 4 fishes was carried out; (3) from April through November 2012, a healthy volunteer study was performed to determine 16:4(n-3) plasma levels after intake of 3 different brands of fish oil or 4 different fish species. Thirty healthy volunteers were randomly selected for the fish oil study; 20 were randomly selected for the fish study. These studies were supported by preclinical tumor experiments in mice to determine chemoresistance conducted between September 2011 and December 2012.(1) Rate of use of fish oil supplements among patients undergoing cancer treatment at our institution; (2) levels of 16:4(n-3) present in 3 brands of fish oil and 4 species of fish; and (3) plasma levels of 16:4(n-3) present in healthy volunteers after consuming fish oil or fish.Eleven percent of respondents reported using omega-3 supplements. All fish oils tested contained relevant amounts of 16:4(n-3), from 0.2 to 5.7 µM. Mouse experiments showed that addition of 1 µL of fish oil to cisplatin was sufficient to induce chemoresistance, treatment having no impact on the growth rate of tumors compared with vehicle-treated controls (estimated tumor volume difference, 44.1 mm3; P > .99). When the recommended daily amount of 10 mL of fish oil was administered to healthy volunteers, rises in plasma 16:4(n-3) levels were observed, reaching up to 20 times the baseline levels. Herring and mackerel contained high levels of 16:4(n-3) in contrast to salmon and tuna. Consumption of fish with high levels of 16:4(n-3) also resulted in elevated plasma levels of 16:4(n-3).All tested fish oils and herring and mackerel fishes contained relevant levels of fatty acid 16:4(n-3), a fatty acid with chemotherapy-negating effects in preclinical models. After ingestion of these fish oils or fishes, 16:4(n-3) was rapidly taken up in the plasma of human volunteers. Until further data become available, fish oil and fish containing high levels of 16:4(n-3) may best be avoided on the days surrounding chemotherapy.
Prolonged Hypercapnia-Evoked Cerebral Hyperemia via K <sup>+</sup> Channel– and Prostaglandin E <sub>2</sub> –Dependent Endothelial Nitric Oxide Synthase Induction
Authors: Taline Najarian, Anne Marilise Marrache, Isabelle Dumont, Pierre Hardy, Martin H. Beauchamp, Xin Hou, Krishna Peri, Fernand Gobeil, Daya R. Varma, Sylvain Chemtob
Journal: Circulation Research (2000)

Abstract —Mechanisms for secondary sustained increase in cerebral blood flow (CBF) during prolonged hypercapnia are unknown. We show that induction of endothelial NO synthase (eNOS) by an increase in prostaglandins (PGs) contributes to the secondary CBF increase during hypercapnic acidosis. Ventilation of pigs with 6% CO 2 (Pa co 2≈ 65 mm Hg; pH ≈7.2) caused a ≈2.5-fold increase in CBF at 30 minutes, which declined to basal values at 3 hours and gradually rose again at 6 and 8 hours; the latter increase was associated with PG elevation, nitrite formation, eNOS mRNA expression, and in situ NO synthase (NOS) reactivity (NADPH-diaphorase staining). Subjecting free-floating brain sections to acidotic conditions increased eNOS expression, the time course of which was similar to that of CBF increase. Treatment of pigs with the cyclooxygenase inhibitor diclofenac or the NOS inhibitor Nω -nitro- l -arginine blunted the initial rise and prevented the secondary CBF increase during hypercapnic acidosis; neuronal NOS blockers 1-(2-trifluoromethylphenyl) imidazole and 3-bromo-7-nitroindazole were ineffective. Diclofenac abolished the hypercapnia-induced rise in cerebrovascular nitrite production, eNOS mRNA expression, and NADPH-diaphorase reactivity. Acidosis (pH ≈7.15, P co 2≈ 40 mm Hg; 6 hours) produced similar increases in prostaglandin E 2 (PGE 2 ) and eNOS mRNA levels in isolated brain microvessels and in NADPH-diaphorase reactivity of brain microvasculature; these changes were prevented by diclofenac, by the receptor-operated Ca 2+ channel blocker SK&amp;F96365, and by the K ATP channel blocker glybenclamide. Acidosis increased Ca 2+ transients in brain endothelial cells, which were blocked by glybenclamide and SK&amp;F96365 but not by diclofenac. Increased PG-related eNOS mRNA and NO-dependent vasorelaxation to substance P was detected as well in rat brain exposed to 6 hours of hypercapnia. PGE 2 was the only major prostanoid that modulated brain eNOS expression during acidosis. Thus, in prolonged hypercapnic acidosis, the secondary CBF rise is closely associated with induction of eNOS expression; this seems to be mediated by PGE 2 generated by a K ATP and Ca 2+ channel–dependent process.
Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy
Authors: Srustidhar Das, Surinder K. Batra
Journal: Cancer Research (2015)

Abstract CA125, the most widely used ovarian cancer biomarker, was first identified approximately 35 years ago in an antibody screen against ovarian cancer antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then, several studies have investigated its expression, functional, and mechanistic involvement in multiple cancer types. Antibody-based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (e.g., oregovomab and abagovomab) have been the modus operandi for MUC16-targeted therapy, but have met with very limited success. In addition, efforts have been also made to disrupt the functional cooperation of MUC16 and its interacting partners; for example, use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell-associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biologic processes involving MUC16 influences our approach toward MUC16-targeted therapy. Cancer Res; 75(22); 4669–74. ©2015 AACR.
Prolonged but reversible sarcolemmal phosphatidyl serine expression in myocardial ischemia represents ischemic memory and can be noninvasively detected by radiolabeled annexin-V imaging
Authors: Leo Hofstra, Ewald Dumont, Artiom Petrov, Navneet Narula, Nezam Haider, Chris Reutelingsperger, Jagat Narula
Journal: Journal of the American College of Cardiology (2003)
Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial
Authors: Ajay Vora, Nick Goulden, Chris Mitchell, Jeremy Hancock, Rachael Hough, Clare Rowntree, Anthony V Moorman, Rachel Wade
Journal: The Lancet Oncology (2014)
PRODUCTION OF ANTIRENIN TO HOMOLOGOUS RENIN AND ITS EFFECT ON EXPERIMENTAL RENAL HYPERTENSION
Authors: Sharad D. Deodhar, Erwin Haas, Harry Goldblatt
Journal: The Journal of Experimental Medicine (1964)

1. Procedures are described for the extraction and partial purification of dog renin, on a large scale, as well as for the acetylation of rat, rabbit, and dog renin. 2. Untreated homologous renin was not antigenic in rat, rabbit, or dog, but the acetylation of homologous renin made it antigenic. 3. Immunization of rats, rabbits, and dogs, with acetylated rat, rabbit, and dog renin, respectively, resulted in each case in the development of anti-renin to the homologous, untreated, as well as to the acetylated renin. 4. The progressive development of antirenin as a result of repeated, subcutaneous injections of acetylated dog renin, in a dog with experimental renal hypertension for more than 6 years, was accompanied by a correspondingly progressive fall of the mean arterial blood pressure to the prehypertensive level. This points up the important part played by the renin-angiotensin mechanism in the maintenance of the hypertension, even in the chronic phase of experimental renal hypertension.
RESPONSE: Re: Association Between Hemochromatosis (HFE) Gene Mutation Carrier Status and the Risk of Colon Cancer
Authors: N. J. Shaheen
Journal: JNCI Journal of the National Cancer Institute (2003)

Shaheen et al.(1) recently reported that carriers of hemochromatosis (HFE) gene mutations have a statistically significantly increased risk of colon cancer.Taken together with other recent findings (2), these results suggest that heterozygosity for hemochromatosis confers increased risk of both colon cancer and cardiovascular disease in the approximately 15% of the U.S. population who are HFE gene mutation carriers.
Polycyclic Aromatic Hydrocarbon-DNA Adducts in Prostate Cancer
Authors: Benjamin A. Rybicki, Andrew Rundle, Adnan T. Savera, Steadman S. Sankey, Deliang Tang
Journal: Cancer Research (2004)

Abstract The formation of DNA adducts can lead to DNA replication errors and the potential for carcinogenesis. DNA adducts have been detected in prostate cells, but the distribution of adducts with respect to prostate cancer risk factors and histology is unknown. In a study of 130 Caucasian (n = 61) and African-American (n = 69) men with prostate cancer who underwent radical prostatectomy, we quantified polycyclic aromatic hydrocarbon (PAH)-DNA adducts in prostate tumor and adjacent nontumor cells by immunohistochemistry. A strong correlation between paired adduct levels in the two cell types was observed (r = 0.56; P &amp;lt; 0.0001); however, nontumor cells had a significantly higher level of adducts compared with tumor (0.30 absorbance units ± 0.05 versus 0.17 absorbance units ± 0.04; P &amp;lt; 0.0001). Variables significantly associated with PAH-DNA adduct levels in tumor cells included primary Gleason grade, tumor volume, and log-transformed prostate-specific antigen (PSA) at time of diagnosis. Tumors with a primary Gleason grade of 5 had significantly lower PAH-DNA adduct levels than tumor cells with a primary Gleason grade of 3 or 4 (P &amp;lt; 0.0001 for both). Tumors that involved 10% or less of the prostate gland had significantly higher PAH-DNA adduct levels than tumors that involved 15 to 20% of the prostate gland (P = 0.004). PSA levels were inversely associated with PAH-DNA adduct levels in tumor cells (P = 0.009). A similar, albeit less significant, inverse association was observed between PSA and PAH-DNA adduct levels in nontumor cells (P = 0.07). Interestingly, increasing primary Gleason grade was associated with increasing PAH-DNA adduct levels in adjacent nontumor cells (P = 0.008). Our results show that PAH-DNA adducts are present in the prostate but vary with regard to cellular histology. In prostate tumor cells, decreased cellular differentiation and increased tumor proliferation may reduce PAH-DNA adduct levels.