tbuckley/cabot-search huggingface dataset:
Single Chemical Modifications of the C-1027 Enediyne Core, a Radiomimetic Antitumor Drug, Affect Both Drug Potency and the Role of Ataxia-Telangiectasia Mutated in Cellular Responses to DNA Double-Strand Breaks
Authors: Daniel R. Kennedy, Loretta S. Gawron, Jianhua Ju, Wen Liu, Ben Shen, Terry A. Beerman
Journal: Cancer Research (2007)

Abstract The radiomimetic enediyne C-1027 induces almost exclusively DNA double-strand breaks (DSB) and is extremely cytotoxic. Unique among radiomimetics, ataxia-telangiectasia mutated (ATM) is dispensable for cellular responses to C-1027-induced DNA damage. This study explores the biological activity of three recently bioengineered C-1027 analogues: 7″-desmethyl-C-1027 (desmethyl), 20′-deschloro-C-1027 (deschloro), and 22′-deshydroxy-C-1027 (deshydroxy). Each compound maintains the characteristic ability of radiomimetics to cleave DNA in cell-free systems, varying in activity from 2-fold (deschloro) to 55-fold (desmethyl) less than C-1027. The induction of cellular DNA breaks based on pulsed field gel electrophoresis, comet analysis, and γH2AX activation was in the same rank order as cell-free DNA break induction, although the amount of breaks induced by desmethyl is greatly reduced compared with the other analogues. Despite the disparity in inducing DNA DSBs, all of the analogues produced G2-M cell cycle arrest and activated DNA DSB damage response proteins, such as p53-Ser15 and Chk2-Thr68, at concentrations in concordance with their ability to inhibit cell growth. Interestingly, of the three analogues, only the desmethyl-induced DNA damage response was similar to C-1027, as it did not cause hypersensitive cell growth inhibition in the absence of ATM nor require the kinase to phosphorylate p53 or Chk2. These findings show that simple modifications of the chromophore of C-1027 can result in varied induction of, and cellular response to, DNA DSBs. [Cancer Res 2007;67(2):773–81]
Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause?
Authors: G Whyte, M Sheppard, K George, R Shave, M Wilson, S Prasad, R O’Hanlon, S Sharma
Journal: British Journal of Sports Medicine (2007)

A growing body of evidence reporting altered cardiac function and myocardial damage after arduous exercise, together with the increased prevalence of arrhythmias observed in highly trained athletes, suggests that repetitive bouts of prolonged, arduous exercise may be deleterious to long-term cardiac health. We report the case of an experienced, highly trained marathon runner who died suddenly while running. On post-mortem examination, left ventricle hypertrophy and idiopathic interstitial myocardial fibrosis was found. We believe that life-long, repetitive bouts of arduous physical activity resulted in fibrous replacement of the myocardium, causing a pathological substrate for the propagation of fatal arrhythmias.
The Antifolate Activity of Tea Catechins
Authors: Mark D. Lucock, Paul D. Roach
Journal: Cancer Research (2005)

To the Editor: In the March 15, 2005, issue of Cancer Research , Navarro-Peran et al. ( [1][1]) described how epigallocatechin gallate (EGCG) inhibits the key folate enzyme dihydrofolate reductase (DHFR).

This study is of tremendous interest. The authors point to the recognized benefits of green
Lack of MEF2A mutations in coronary artery disease
Authors: Li Weng, Nihan Kavaslar, Anna Ustaszewska, Heather Doelle, Wendy Schackwitz, Sybil Hébert, Jonathan C. Cohen, Ruth McPherson, Len A. Pennacchio
Journal: Journal of Clinical Investigation (2005)

Mutations in MEF2A have been implicated in an autosomal dominant form of coronary artery disease (adCAD1). In this study we sought to determine whether severe mutations in MEF2A might also explain sporadic cases of coronary artery disease (CAD). To do this, we resequenced the coding sequence and splice sites of MEF2A in approximately 300 patients with premature CAD and failed to find causative mutations in the CAD cohort. However, we did identify the 21-bp MEF2A coding sequence deletion originally implicated in adCAD1 in 1 of 300 elderly control subjects without CAD. Further screening of approximately 1,500 additional individuals without CAD revealed 2 more subjects with the MEF2A 21-bp deletion. Genotyping of 19 family members of the 3 probands with the 21-bp deletion in MEF2A revealed that the mutation did not cosegregate with early CAD. These studies support that MEF2A mutations are not a common cause of CAD in white people and argue strongly against a role for the MEF2A 21-bp deletion in autosomal dominant CAD.
Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis.
Authors: C M Coughlin, K E Salhany, M Wysocka, E Aruga, H Kurzawa, A E Chang, C A Hunter, J C Fox, G Trinchieri, W M Lee
Journal: Journal of Clinical Investigation (1998)

The antitumor effect and mechanisms activated by murine IL-12 and IL-18, cytokines that induce IFN-gamma production, were studied using engineered SCK murine mammary carcinoma cells. In syngeneic A/J mice, SCK cells expressing mIL-12 or mIL-18 were less tumorigenic and formed tumors more slowly than control cells. Neither SCK.12 nor SCK.18 cells protected significantly against tumorigenesis by distant SCK cells. However, inoculation of the two cell types together synergistically protected 70% of mice from concurrently injected distant SCK cells and 30% of mice from SCK cells established 3 d earlier. Antibody neutralization studies revealed that the antitumor effects of secreted mIL-12 and mIL-18 required IFN-gamma. Interestingly, half the survivors of SCK.12 and/or SCK.18 cells developed protective immunity suggesting that anti-SCK immunity is unlikely to be responsible for protection. Instead, angiogenesis inhibition, assayed by Matrigel implants, appeared to be a property of both SCK.12 and SCK.18 cells and the two cell types together produced significantly greater systemic inhibition of angiogenesis. This suggests that inhibition of tumor angiogenesis is an important part of the systemic antitumor effect produced by mIL-12 and mIL-18.
Adenoidectomy versus chemoprophylaxis and placebo for recurrent acute otitis media in children aged under 2 years: randomised controlled trial
Authors: Petri Koivunen, Matti Uhari, Jukka Luotonen, Aila Kristo, Risto Raski, Tytti Pokka, Olli-Pekka Alho
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To evaluate the efficacy of adenoidectomy compared with long term chemoprophylaxis and placebo in the prevention of recurrent acute otitis media in children aged between 10 months and 2 years. <b>Design</b> Randomised, double blind, controlled trial. <b>Setting</b> Oulu University Hospital, a tertiary centre in Finland. <b>Participants</b> 180 children aged 10 months to 2 years with recurrent acute otitis media. <b>Intervention</b> Adenoidectomy, sulfafurazole (sulphisoxazole) 50 mg/kg body weight, given once a day for six months or placebo. Follow up lasted for two years, during which time all symptoms and episodes of acute otitis media were recorded. <b>Main outcome measures</b> Intervention failure (two episodes in two months or three in six months or persistent effusion) during follow up, number of episodes of acute otitis media, number of visits to a doctor because of any infection, and antibiotic prescriptions Number of prescriptions, and days with symptoms of respiratory infection. <b>Results</b> Compared with placebo, interventions failed during both the first six months and the rest of the follow up period of 24 months similarly in the adenoidectomy and chemoprophylaxis groups (at six months the differences in risk were 10% (95% confidence interval −9% to 29%) and 18% (−2% to 38%), respectively). No significant differences were observed between the groups in the numbers of episodes of acute otitis media, visits to a doctor, antibiotic prescriptions, and days with symptoms of respiratory infection. <b>Conclusions</b> Adenoidectomy, as the first surgical treatment of children aged 10 to 24 months with recurrent acute otitis media, is not effective in preventing further episodes. It cannot be recommended as the primary method of prophylaxis.
Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery
Authors: Steven G. Coca, Amit X. Garg, Heather Thiessen-Philbrook, Jay L. Koyner, Uptal D. Patel, Harlan M. Krumholz, Michael G. Shlipak, Chirag R. Parikh
Journal: Journal of the American Society of Nephrology (2013)

Urinary biomarkers of AKI provide prognostic value for in-hospital outcomes, but little is known about their association with longer-term mortality after surgery. We sought to assess the association between kidney injury biomarkers and all-cause mortality in an international, multicenter, prospective long-term follow-up study from six clinical centers in the United States and Canada composed of 1199 adults who underwent cardiac surgery between 2007 and 2009 and were enrolled in the Translational Research in Biomarker Endpoints in AKI cohort. On postoperative days 1–3, we measured the following five urinary biomarkers: neutrophil gelatinase-associated lipocalin, IL-18, kidney injury molecule-1 (KIM-1), liver fatty acid binding protein, and albumin. During a median follow-up of 3.0 years (interquartile range, 2.2–3.6 years), 139 participants died (55 deaths per 1000 person-years). Among patients with clinical AKI, the highest tertiles of peak urinary neutrophil gelatinase-associated lipocalin, IL-18, KIM-1, liver fatty acid binding protein, and albumin associated independently with a 2.0- to 3.2-fold increased risk for mortality compared with the lowest tertiles. In patients without clinical AKI, the highest tertiles of peak IL-18 and KIM-1 also associated independently with long-term mortality (adjusted hazard ratios [95% confidence intervals] of 1.2 [1.0 to 1.5] and 1.8 [1.4 to 2.3] for IL-18 and KIM-1, respectively), and yielded continuous net reclassification improvements of 0.26 and 0.37, respectively, for the prediction of 3-year mortality. In conclusion, urinary biomarkers of kidney injury, particularly IL-18 and KIM-1, in the immediate postoperative period provide additional prognostic information for 3-year mortality risk in patients with and without clinical AKI.
Effects of vasopressin and prostaglandin E1 on the adenyl cyclase—cyclic 3′,5′-adenosine monophosphate system of the renal medulla of the rat
Authors: Nama P. Beck, Toshio Kaneko, Uriel Zor, James B. Field, Bernard B. Davis
Journal: Journal of Clinical Investigation (1971)

Vasopressin increased adenyl cyclase activity in homogenates of both inner and outer renal medulla of the rat. It also increased the concentration of cyclic 3',5'-adenosine monophosphate (AMP) in slices of both inner and outer medulla but not in renal cortex. In the inner medulla, a concentration of prostaglandin E(1) (PGE(1)), which was ineffective by itself significantly reduced the stimulation of adenyl cyclase activity and cyclic AMP concentration induced by vasopressin. These results are consistent with the hypothesis that PGE(1) can compete with vasopressin for adenyl cyclase-binding sites. However, the findings in the outer medulla suggest the situation is more complex. Although 10(-8) M PGE(1) had no effect by itself and inhibited the vasopressin-induced elevation of cyclic AMP, larger amounts of PGE(1) increased both adenyl cyclase activity and cyclic AMP levels. The maximum effect on the latter parameter was at least 6 times as great as that of maximum amounts of vasopressin.
In Vivo Potentiation of 5-Fluorouracil Cytotoxicity Against AKR Leukemia by Purines, Pyrimidines, and Their Nucleosides and Deoxynucleosides&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: G Santelli, F Valeriote
Journal: JNCI Journal of the National Cancer Institute (1980)

The effect of various natural pyrimidines and purines and their nucleosides and deoxynucleosides on 5-fluorouracil (FUra) cytotoxicity was examined against the transplantable AKR leukemia in female AKR mice. The spleen colony assay was used for a quantitative evaluation of the antitumor activity of the combination treatments. The base or nucleoside was administered 15 minutes before each mouse received an injection of 0.6 mg FUra. All of the compounds tested, with the exception of adenine, potentiated the cell-killing effect of FUra. On a molar basis (16-30 mumol/mouse), thymine, uracil, thymidine, and uridine enhanced FUra cytotoxicity more than a hundredfold. 2'-Deoxyuridine and the purine nucleosides and deoxynucleosides had similar potentiating activities between tenfold and fortyfold at 30 mumol per mouse. Finally, glucose, also administered 15 minutes before each mouse received an injection of 0.6 mg FUra, enhanced the antitumor activity of the drug by a factor of about five.
Gap Junction Blockers Decrease Defibrillation Thresholds Without Changes in Ventricular Refractoriness in Isolated Rabbit Hearts
Authors: Xiangqian Qi, Pryamvada Varma, David Newman, Paul Dorian
Journal: Circulation (2001)

Background The maintenance and termination of reentry arrhythmias are determined by tissue properties such as refractoriness and conduction velocity. Although the effects of Na + and K + channel block on electrophysiological properties and defibrillation threshold (DFT) have been studied, little is known about the effect of gap junction blockers on defibrillation and tissue electrophysiological properties. Methods and Results Triplicate DFTs (volts) were obtained before and 15 minutes after 4 μmol/L 16-doxyl-stearic acid (16-DSA, n=8), 1 mmol/L 1-heptanol (n=12) (both gap junction blockers), 3 μg/mL lidocaine (a sodium channel blocker) (n=8), and respective controls (n=27) in isolated perfused rabbit hearts. DFT decreased after 16-DSA (23±14%, P &lt;0.01) and 1-heptanol (21±16%, P &lt;0.01) but increased after lidocaine (26±28%, P &lt;0.05). Ventricular fibrillation cycle length (VFCL) and QRS duration increased after all 3 agents, by 36±19% and 44±16% (16-DSA), 87±42% and 49±15% (heptanol), and 57±20% and 43±26% (lidocaine), respectively (all P &lt;0.01). Spatially averaged temporal VFCL dispersion decreased significantly after all 3 agents, by 47±42% (16-DSA, P &lt;0.05), 74±19% (1-heptanol, P &lt;0.01), and 82±13% (lidocaine, P &lt;0.01), respectively. Ventricular effective refractory period and monophasic action potential duration at 90% repolarization were unchanged after 16-DSA and 1-heptanol ( P =NS) but increased after lidocaine (16±13%, P &lt;0.01, and 6±5%, P =NS, respectively). There were no significant changes in DFT or any other electrophysiological variable in control hearts. Conclusions Electrical uncoupling by 16-DSA and 1-heptanol significantly lowers DFT and dispersion of VFCL without altering refractoriness; lidocaine, at doses resulting in similar slowing of conduction, increases DFT.
Brain damage and mortality in dogs following pulsatile and non-pulsatile blood flows in extracorporeal circulation
Authors: G. Wright, J. M. Sanderson
Journal: Thorax (1972)

In a series of 20 dog experiments, total cardiac bypass was followed by a high rate of mortality during the first 12 postoperative hours. Only five dogs survived for one week, but a further three dogs were perfuse-fixed after shorter periods of survival. All dogs developed pulmonary alveolar haemorrhages and seven of the eight perfuse-fixed brains exhibited brain damage. Diffuse nerve cell changes were found in the brains of dogs subjected to non-pulsatile blood flow. Focal brain lesions were found following both pulsatile and non-pulsatile blood flows. The lesions varied from staining pallor and rarefaction of the neuropil to total nerve cell loss and glial infiltration depending upon the duration of survival. When considered in conjunction with a previous series of experiments, these results show that the diffuse nerve cell changes associated with roller pump perfusions can be avoided by using a new pulsatile pump, but focal brain damage was not eliminated, and lung damage and mortality were not reduced.
Transgenic Overexpression of GATA-3 in T Lymphocytes Improves Autoimmune Glomerulonephritis in Mice with a BXSB/MpJ-Yaa Genetic Background
Authors: Keigyou Yoh, Kazuko Shibuya, Naoki Morito, Takako Nakano, Kazusa Ishizaki, Homare Shimohata, Masato Nose, Shozo Izui, Akira Shibuya, Akio Koyama, James Douglas Engel, Masayuki Yamamoto, Satoru Takahashi
Journal: Journal of the American Society of Nephrology (2003)

A T helper 1 (Th1)/Th2 imbalance is thought to contribute to the pathogenesis of autoimmune diseases. The differentiation of T cells into Th1 or Th2 subtypes is under the regulation of several transcription factors. Among these, transcription factor GATA-3 is thought to play an indispensable role in the development of T cells and the differentiation of Th2 cells. To examine how a Th1/Th2 imbalance affects the development of autoimmune disease, GATA-3 was overexpressed in the T lymphocytes of C57BL/6 x BXSB/MpJ-Yaa F(1) (Yaa) mice. Yaa mice developed autoimmune nephritis similarly to BXSB/MpJ-Yaa mice, which are commonly used as a model for Th1-dominant murine lupus. GATA-3 overexpression in T cells improved the 50% mortality incidence time for GATA-3-transgenic Yaa mice (41.6 wk), compared with Yaa mice (30.9 wk), and reduced proteinuria, serum creatinine levels, and the severity of glomerulonephritis in GATA-3-transgenic Yaa mice. GATA-3 overexpression in Yaa mice led to simultaneously elevated Th2 Ig (IgG1) and decreased Th1 Ig (IgG2a and IgG3) production and serum IFN-gamma levels. Although IL-4 production remained unchanged, intracellular cytokine analyses demonstrated that IL-5 was induced and IFN-gamma was suppressed in stimulated T cells from the GATA-3-transgenic Yaa mice. These results indicated that abundant GATA-3 was unable to stimulate complete differentiation of Th2 cells but did counteract the dominance of Th1 cells and alleviated the disease severity in Yaa mice. These data suggest that transcriptional regulation therapy may have potential as an effective strategy for treating autoimmune glomerulonephritis.
Tobacco Industry Promotion of Cigarettes and Adolescent Smoking
Authors: J P Pierce, W S Choi, E A Gilpin, A J Farkas, C C Berry
Journal: JAMA (1998)

Context.—Whether tobacco advertising and promotion increases the likelihood that youths will begin smoking has important public policy implications.Objective.—To evaluate the association between receptivity to tobacco advertising and promotional activities and progress in the smoking uptake process, defined sequentially as never smokers who would not consider experimenting with smoking, never smokers who would consider experimenting, experimenters (smoked at least once but fewer than 100 cigarettes), or established smokers (smoked at least 100 cigarettes).Design.—Prospective cohort study with a 3-year follow-up through November 1996.Setting and Participants.—A total of 1752 adolescent never smokers who were not susceptible to smoking when first interviewed in 1993 in a population-based random-digit dial telephone survey in California were reinterviewed in 1996.Main Outcome Measure.—Becoming susceptible to smoking or experimenting by 1996.Results.—More than half the sample (n=979) named a favorite cigarette advertisement in 1993 and Joe Camel advertisements were the most popular. Less than 5% (n=92) at baseline possessed a promotional item but a further 10% (n=172) were willing to use an item. While having a favorite advertisement in 1993 predicted which adolescents would progress by 1996 (odds ratio [OR] =1.82; 95% confidence interval [CI], 1.04-3.20), possession or willingness to use a promotional item was even more strongly associated with future progression (OR=2.89; 95% CI, 1.47-5.68). From these data, we estimate that 34% of all experimentation in California between 1993 and 1996 can be attributed to tobacco promotional activities. Nationally, this would be over 700000 adolescents each year.Conclusion.—These findings provide the first longitudinal evidence to our knowledge that tobacco promotional activities are causally related to the onset of smoking.
Liposome-Encapsulated CpG Oligodeoxynucleotides as a Potent Adjuvant for Inducing Type 1 Innate Immunity
Authors: Yoshinori Suzuki, Daiko Wakita, Kenji Chamoto, Yoshinori Narita, Takemasa Tsuji, Tsuguhide Takeshima, Hiroshi Gyobu, You Kawarada, Satoshi Kondo, Shizuo Akira, Hiroyuki Katoh, Hiroaki Ikeda, Takashi Nishimura
Journal: Cancer Research (2004)

Abstract Unmethylated cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs) exhibit potent immunostimulating activity by binding with Toll-like receptor 9 (TLR9) expressed on antigen-presenting cells. Here, we show that CpG-ODN encapsulated in cationic liposomes (CpG-liposomes) improves its incorporation into CD11c+ dendritic cells (DCs) and induces enhanced serum interleukin (IL)-12 levels compared with unmodified CpG-ODN. CpG-liposome potently activated natural killer (NK) cells (84.3%) and NKT cells (48.3%) to produce interferon-γ (IFN-γ), whereas the same dose of unmodified CpG-ODN induced only low numbers of IFN-γ–producing NK cells (12.7%) and NKT cells (1.6%) to produce IFN-γ. In contrast with the NKT cell agonist α-galactosylceramide, which induces both IFN-γ and IL-4 production by NKT cells, CpG-liposome only induced IFN-γ production by NKT cells. Such potent adjuvant activities of CpG-liposome were absent in TLR9-deficient mice, indicating that CpG-liposome was as effective as CpG-ODN in stimulating type 1 innate immunity through TLR9. In addition to TLR9, at least two other factors, IL-12 production by DCs and direct contact between DCs and NK or NKT cells, were essential for inducing type 1 innate immunity by CpG-liposome. Furthermore, ligation of TLR9 by CpG-liposome coencapsulated with ovalbumin (OVA) caused the induction of OVA-specific CTLs, which exhibited potent cytotoxicity against OVA-expressing tumor cells. These results indicate that CpG-liposome alone or combined with tumor antigen protein provides a promising approach for the prevention or therapy of tumors.
Hospitalization Rates Among Survivors of Young Adult Malignancies
Authors: Devon P. Richardson, Corinne Daly, Rinku Sutradhar, Lawrence F. Paszat, Andrew S. Wilton, Linda Rabeneck, Nancy N. Baxter
Journal: Journal of Clinical Oncology (2015)

There are limited data on health care use among survivors of young adult cancers. We aimed to describe patterns of hospitalization among a cohort of long-term survivors compared with noncancer controls.Persons diagnosed between the ages of 20 and 44 years with malignancies in Ontario, Canada, from 1992 to 1999, who lived at least 5 years recurrence free, were identified using the Ontario Cancer Registry and matched to noncancer controls. Hospitalizations were determined using hospital discharges, and rates were compared between survivors and controls. The absolute excess rate of hospitalizations was determined for each type of malignancy in survivors per 100 person-years of follow-up.The cohort included 20,275 survivors and 101,344 noncancer controls. During the study period, 6,948 (34.3%) survivors were admitted to the hospital and the adjusted relative rate (ARR) of hospitalizations in survivors compared with controls was 1.51 (95% CI, 1.48 to 1.54). The rate of hospitalization was highest for survivors of upper GI, leukemia, and urologic malignancies. The hospitalization rate (per person) for survivors significantly decreased from 0.22 in the first time period examined (5 to 8 years after diagnosis) to 0.15 in the last time period examined (18 to 20 years after diagnosis, P < .0001). However, at all time periods, survivors were more likely to be hospitalized than controls (ARR at 5 to 8 years, 1.67 [95% CI, 1.57 to 1.81]; ARR at 18 to 20 years, 1.22 [95% CI, 1.08 to 1.37]).Survivors of young adult cancers have an increased rate of hospitalization compared with controls. The rate of hospitalization for 20-year survivors did not return to baseline, indicating a substantial and persistent burden of late effects among this generally young population.