Cancer-Free Survival Following Alemtuzumab Induction in Heart Transplantation

Background

The malignancy rate after alemtuzumab (C-1H) induction in cardiac transplantation is unknown.

Methods

A retrospective analysis from a single center for all patients that underwent cardiac transplantation from January 2000 to January 2011 and that had no history of malignancy before transplantation was performed. Patients induced with alemtuzumab were compared with a group of patients receiving thymoglobulin or no induction and assessed for 4-year cancer-free post–heart transplantation survival.

Results

Of 402 patients included, 185 (46.0%) received alemtuzumab, 56 (13.9%) thymoglobulin, and 161 (40.0%) no induction. Baseline characteristics did not differ between groups: mean age 54.0 years, male 77.1%, white 88.6%, ischemic cardiomyopathy 49.0%. The calcineurin inhibitor was tacrolimus in 98.9% of alemtuzumab patients, 98.2% of thymoglobulin patients, and 87.0% of the noninduced (P < .001). The secondary agent was mycophenolate mofetil in all but 16 noninduced patients (9.9%), who received azathioprine. The 4-year cancer-free survival did not differ between groups: 88.1% alemtuzumab, 87.5% thymoglobulin, 88.2% noninduction; P = .088. The 4-year nonskin cancer–free survival was 96.8% for the alemtuzumab group, 96.4% for the thymoglobulin group, and 95.7% for the noninduced; P = .899.

Conclusions

Neither the 4-year cancer-free survival nor the 4-year nonskin cancer–free survival differed between the alemtuzumab, thymoglobulin, and noninduced groups.     

Synthesis of [3H], [13C3, 15N], and [14C]SCH 900567: an inhibitor of TNF‐α (tumor necrosis factor alpha) converting enzyme (TACE)

SCH 900567 is a specific inhibitor of tumor necrosis factor‐alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [³H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope‐labeled [¹³C₃, ¹⁵N]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [¹³C₃, ¹⁵N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [¹⁴C]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [¹⁴C]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.     

Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

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Share or perish: Social media and the International Journal of Mental Health Nursing

The impact of published research is sometimes measured by the number of citations an individual article accumulates. However, the time from publication to citation can be extensive. Years may pass before authors are able to measure the impact of their publication. Social media provides individuals and organizations a powerful medium with which to share information. The power of social media is sometimes harnessed to share scholarly works, especially journal article citations and quotes. A non‐traditional bibliometric is required to understand the impact social media has on disseminating scholarly works/research. The International Journal of Mental Health Nursing (IJMHN) appointed a social media editor as of 1 January 2017 to implement a strategy to increase the impact and reach of the journal's articles. To measure the impact of the IJMHN social media strategy, quantitative data for the eighteen months prior to the social media editor start date, and the eighteen months after that date (i.e.: from 01 July 2015 to 30 June 2018) were acquired and analysed. Quantitative evidence demonstrates the effectiveness of one journal's social media strategy in increasing the reach and readership of the articles it publishes. This information may be of interest to those considering where to publish their research, those wanting to amplify the reach of their research, those who fund research, and journal editors and boards.     

Hyperhomocysteinemia exacerbates the development of intimal hyperplasia in Sprague-Dawley rats: Alleviation by rosiglitazone

The amino acid intermediate homocysteine (Hcy) is formed during the metabolism of methionine to cysteine. Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for coronary atherosclerosis. The circulating levels of total Hcy (tHcy) can increase due to intake of foods rich in methionine or deficiencies of vitamins such as folate, pyridoxine and cyanocobalamin, which are required for the metabolism of Hcy. In addition, mutations in the genes coding for Hcy metabolizing enzymes can contribute to an increase in tHcy levels. Clinical and epidemiological studies have shown that an elevated level of tHcy measured in serum or plasma is a strong predictor of cardiovascular disease risk, which appears to be greatest in patients who have HHcy following a methionine load. Intimal hyperplasia (IH) (intima/media [I/M] ratio) is the universal response of a vessel to injury and may result in vasoconstriction when left unattended. The effect of dietary HHcy on balloon catheter-injured carotid artery and its modulation (if any) by the peroxisome proliferator-activated receptor agonist gamma rosiglitazone was evaluated in 12-week-old female Sprague-Dawley rats fed either a control diet or a diet containing 1% L-methionine. Once the rats were established on the diet, the group that was fed 1% L-methionine was further subdivided and either given an aqueous preparation of 3 mg/kg/day rosiglitazone or the vehicle via oral gavage for one week. This was followed by surgically injuring the left carotid artery using a Maverick Over-The-Wire catheter (2.0 mm × 20 mm, 3.2F; Boston Scientific, USA). The rats were continued on their respective diets and drug regimen for 21 days postsurgery. On day 22 of the procedure, the rats were sacrificed for collection of blood, the carotid arteries and liver for biochemical and histological evaluation. Compared with controls there was a significant increase in both tHcy levels and I/M ratio in the rats fed 1% L-methionine (5.4±0.28 μM versus 32.8±3.01 μM, P<0.002; and 0.175±0.05 versus 1.05±0.23, P<0.005, respectively). The effect of rosiglitazone in rats fed the control diet was not prominent. On the other hand, administration of rosiglitazone to the rats on the 1% L-methionine diet significantly reduced the levels of serum tHcy (16.6±2.1 μM versus 32.8±3.01 μM, P<0.001); however, the tHcy levels remained significantly elevated compared with animals on the control diet (P<0.002). The group receiving the L-methionine diet plus rosiglitazone had an inhibition in the development of IH compared with those receiving the L-methionine diet alone (I/M of 0.278±0.041 versus 1.05±0.23, P<0.01). Moreover, the development of IH in the group receiving the L-methionine diet plus rosiglitazone treatment was not significantly different from that observed in the group on the control diet without rosiglitazone (0.278±0.041 versus 0.175±0.05, respectively). These findings may have important implications in deciphering the molecular mechanisms involved in the augmentation of IH in HHcy and modulation of this process by rosiglitazone.     

Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.

The prevalence of abnormalities of lipoprotein cholesterol and apolipoproteins A-I and B and lipoprotein (a) [Lp(a)] was determined in 321 men (mean age 50 +/- 7 years) with angiographically documented coronary artery disease and compared with that in 901 control subjects from the Framingham Offspring Study (mean age 49 +/- 6 years) who were clinically free of coronary artery disease. After correction for sampling in hospital, beta-adrenergic medication use and effects of diet, patients had significantly higher cholesterol levels (224 +/- 53 vs. 214 +/- 36 mg/dl), triglycerides (189 +/- 95 vs. 141 +/- 104 mg/dl), low density lipoprotein (LDL) cholesterol (156 +/- 51 vs. 138 +/- 33 mg/dl), apolipoprotein B (131 +/- 37 vs. 108 +/- 33 mg/dl) and Lp(a) levels (19.9 +/- 19 vs. 14.9 +/- 17.5 mg/dl). They also had significantly lower high density lipoprotein (HDL) cholesterol (36 +/- 11 vs. 45 +/- 12 mg/dl) and apolipoprotein A-I levels (114 +/- 26 vs. 136 +/- 32 mg/dl) (all p less than 0.005). On the basis of Lipid Research Clinic 90th percentile values for triglycerides and LDL cholesterol and 10th percentile values for HDL cholesterol, the most frequent dyslipidemias were low HDL cholesterol alone (19.3% vs. 4.4%), elevated LDL cholesterol (12.1% vs. 9%), hypertriglyceridemia with low HDL cholesterol (9.7% vs. 4.2%), hypertriglyceridemia and elevated LDL cholesterol with low HDL cholesterol (3.4% vs. 0.2%) and Lp(a) excess (15.8% vs. 10%) in patients versus control subjects, respectively (p less than 0.05). Stepwise discriminant analysis indicates that smoking, hypertension, decreased apolipoprotein A-I, increased apolipoprotein B, increased Lp(a) and diabetes are all significant (p less than 0.05) factors in descending order of importance in distinguishing patients with coronary artery disease from normal control subjects. Not applying a correction for beta-adrenergic blocking agents, sampling bias and diet effects leads to a serious underestimation of the prevalence of LDL abnormalities and an overestimation of HDL abnormalities in patients with coronary artery disease. However, 35% of patients had a total cholesterol level less than 200 mg/dl after correction; of those patients, 73% had an HDL cholesterol level less than 35 mg/dl.     

Measurement of cholesterol synthesis in man by isotope kinetics of squalene.

A method for measuring the rate of total daily cholesterol synthesis in man has been developed through isotope kinetic studies of squalene biosynthesis after intravenous administration of [14C]mevalonic acid. Plasma squalene becomes rapidly labeled, reaching maximal specific activity approximately 100 min after mevalonate administration and then decays exponentially to reach undetectable levels in 12 hr. The rate of daily squalene synthesis equals the percent dose of mevalonate converted to cholesterol divided by the area under the specific activity curve of squalene; the fraction of the dose of mevalonate converted to cholesterol is calculated by the simultaneous injection of [3H]- and [14C] cholesterol in plasma. The premise that squalene and cholesterol synthetic rates are equivalent was tested. In seven patients it was found that the mean daily cholesterol synthesis rates estimated simultaneously by sterol balance and by sqyalene kinetic methods agreed within 8%. In addition, fractional conversions of mevalonic acid to cholesterol were highly correlated with cholesterol synthesis rates. Maximum estimates of the pool sizes and half-lives of metabolically "active" squalene also were obtained. This measurement of daily cholesterol synthesis by squalene kinetics minimizes patient inconvenience, is suitable for outpatient studies, and yields results in 4 weeks or less. Because of the rapidity of the rate of squalene synthesis, the results obtained reflect cholesterol synthesis over a period of less than 10 hr and are therefore uniquely applicable to unsteady state situations.