Citations

Abstract Purpose: Osteosarcoma most commonly recurs in the lung. Based on preliminary data on the antitumor effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in animal models, and promising phase I trials, we embarked on a feasibility study of inhaled GM-CSF in patients with first isolated pulmonary recurrence of osteosarcoma. Experimental Design: Forty-three eligible patients received inhaled GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks. Following two cycles, patients underwent thoracotomy to resect tumor and analyze pulmonary nodules for expression of Fas/Fas ligand (Fas/FasL), and the presence of dendritic cells by immunostaining for CD1a, clusterin, and S100. Following surgery, patients received 12 additional cycles of therapy on alternating weeks or until progression. Event-free survival and survival, and feasibility of therapy delivery were evaluated. Results: Dose escalation to 1,750 μg twice daily was feasible with no dose-limiting toxicity. Mean scores for Fas/FasL in nodules from patients with bilateral recurrence who underwent unilateral thoracotomy pretreatment (using a scoring system of 0-3) were 1.3 and 0.88, respectively, compared with 0.78 and 0.62 in nodules resected following two cycles of therapy. Only 11 of 30 nodules postinhalation were positive for CD1a, 4 of 30 for S100, and 6 of 30 for clusterin. Event-free and overall survival at 3 years were 7.8% and 35.4%, respectively. Conclusions: Inhalation of GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks was feasible with low toxicity. However, no detectable immunostimulatory effect in pulmonary metastases or improved outcome postrelapse was seen. Clin Cancer Res; 16(15); 4024–30. ©2010 AACR.

Background— Circadian rhythms with regard to time of symptom onset for patients with acute myocardial infarction have been observed, although their relationship to outcomes has been debated. We evaluated these rhythms in patients with ST-elevation myocardial infarction as a function of the 24-hour circadian cycle. Methods and Results— The relationship between onset of symptoms during the 24-hour circadian cycle and prehospital delays from symptom onset to hospital arrival, timeliness of reperfusion, and in-hospital death was assessed in 2143 patients with ST-elevation myocardial infarction presenting from 2004–2008 at 1 of 3 tertiary-care healthcare ST-elevation myocardial infarction systems. There was a significant association between time of onset and the circadian cycle, with the greatest percentage (39%) of patients experiencing onset between 8 am and 3 pm ( P <0.001). Time of onset was associated with prehospital delay and timeliness of reperfusion. Patients with onset from 12 am to 5:59 am had median prehospital delays of 121 minutes versus 70 minutes from 12 pm to 5:59 pm ( P <0.001). Patients with onset time from 12 am to 5:59 am had median door-to-balloon times of 75 minutes versus 60 minutes from 6 am to 11:59 am ( P <0.001). Using multivariable modeling to control for baseline patient characteristics, prehospital delay, and timeliness of reperfusion, there was no significant association between time of symptom onset with in-hospital death. Conclusions— Patients with ST-elevation myocardial infarction exhibit significant circadian patterns in symptom onset, prehospital delay, and timeliness of reperfusion. Patients who develop symptoms from 12 am to 5:59 am present with longer prehospital delays and have longer door-to-balloon times. After multivariable adjustment, there was no significant association between circadian patterns of time of onset and in-hospital death.

Abstract The expression of pathogen recognition receptors in human FOXP3+ T regulatory cells is established, yet the function of these receptors is currently obscure. In the process of studying the function of both peripheral and lamina propria FOXP3+ lymphocytes in patients with the human inflammatory bowel disease Crohn’s disease, we observed a clear deficiency in the quantity of FOXP3+ lymphocytes in patients with disease-associated polymorphisms in the pathogen recognition receptor gene NOD2. Subsequently, we determined that the NOD2 ligand, muramyl dipeptide (MDP), activates NF-κB in primary human FOXP3+ T cells. This activation is functionally relevant, as MDP-stimulated human FOXP3+ T cells are protected from death receptor Fas-mediated apoptosis. Importantly, apoptosis protection was not evident in MDP-stimulated FOXP3+ T cells isolated from a patient with the disease-associated polymorphism. Thus, we propose that one function of pathogen recognition receptors in human T regulatory cells is the protection against death receptor-mediated apoptosis in a Fas ligand-rich environment, such as that of the inflamed intestinal subepithelial space.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Background— In 2000, the definition of myocardial infarction (MI) changed to rely on troponin rather than creatine kinase (CK) and its MB fraction (CK-MB). The implications of this change on trends in MI incidence and outcome are not defined. Methods and Results— This was a community study of 2816 patients hospitalized with incident MI from 1987 to 2006 in Olmsted County, Minnesota, with prospective measurements of troponin and CK-MB from August 2000 forward. Outcomes were MI incidence, severity, and survival. After troponin was introduced, 278 (25%) of 1127 incident MIs met only troponin-based criteria. When cases meeting only troponin criteria were included, incidence did not change between 1987 and 2006. When restricted to cases defined by CK/CK-MB, the incidence of MI declined by 20%. The incidence of non–ST-segment elevation MI increased markedly by relying on troponin, whereas that of ST-segment elevation MI declined regardless of troponin. The age- and sex-adjusted hazard ratio of death within 30 days for an infarction occurring in 2006 (compared with 1987) was 0.44 (95% confidence interval, 0.30 to 0.64). Among 30-day survivors, survival did not improve, but causes of death shifted from cardiovascular to noncardiovascular ( P =0.001). Trends in long-term survival among 30-day survivors were similar regardless of troponin. Conclusions— Over the last 2 decades, a substantial change in the epidemiology of MI occurred that was only partially mediated by the introduction of troponin. Non–ST-segment elevation MIs now constitute the majority of MIs. Although the 30-day case fatality improved markedly, long-term survival did not change, and the cause of death shifted from cardiovascular to noncardiovascular.

Abstract The effects of castration on bone histomorphometry and mineral homeostasis were compared in male and female rats. Measurements were performed 4 weeks after sham operation or gonadectomy. Orchiectomy produced increases in serum calcium and decreases in serum testosterone and androstenedione, whereas ovariectomy produced decreases in serum estradiol and testosterone. Orchiectomy did not alter static bone histomorphometric measurements of the tibial diaphysis, whereas ovariectomy increased cross-sectional and medullary areas, lowered endosteal tetracycline-labeled surface length, and markedly increased endosteal nonlabeled surface length. Orchiectomy decreased mean periosteal bone formation rate and mean periosteal bone apposition rate, whereas ovariectomy increased both measurements. Orchiectomy and ovariectomy markedly diminished trabecular area and trabecular surface length at the tibial metaphysis. Orchiectomy did not alter the number of osteoclasts per mm trabecular surface or the percentage of trabecular surface covered by osteoclasts, whereas ovariectomy increased both measurements. These findings indicate that gonadal hormones produce separate and distinct effects on bone metabolism as determined by histomorphometry in male and female rats.

Abstract The effects of fluoride at concentrations of 2.0 and 4.5 mM in drinking water on growth rate, vitamin D, water and mineral metabolism, bone histomorphometry, and osteoinduction of demineralized allogenic bone matrix (DABM) were compared in the rat. Whereas fluoride did not influence fluid intake or growth rate at the lower concentration, it increased fluid intake and inhibited growth rate at the higher concentration. Fluoride produced dose-related increases in serum fluoride and alkaline phosphatase but did not alter serum 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D. Serum calcium and phosphate were reduced by fluoride at concentrations of 2.0 mM but not 4.5 mM. Cancellous bone fractional area was increased by fluoride at 2.0 mM and was reduced by fluoride at 4.5 mM. Fluoride had no effect on cancellous bone surface length or the percentage surface lined by osteoblasts and osteoclasts. Fluoride increased medullary area and decreased the endosteal bone formation rate. Fluoride increased periosteal bone formation and apposition rates at concentrations of 2.0 mM but not 4.5 mM. Fluoride inhibited mineralization in DABM implants, and at the higher concentration, fluoride increased the formation of new bone matrix. These results indicate that in the rat, fluoride increases cortical and trabecular bone at therapeutic doses and reduces trabecular bone at toxic doses. The serum concentration of flouride at therapeutic doses in the rat is similar to that in patients with osteoporosis who are on treatment with fluoride. In the rat, there is a narrow range between toxic and therapeutic doses.

Abstract Gallium nitrate lowers the serum calcium in patients with hypercalcemia caused by malignancy and is available for clinical use. The mechanism for the hypocalcemic action is unknown, however. The present studies were undertaken to determine the effects of gallium on bone metabolism. Normal male rats were implanted subcutaneously with mineralized allogeneic bone matrix. Histomorphometry of the implants and of tibiae was determined after three doses of tetracycline administered at intervals of 1 week. Gallium as nitrate was administered daily by intraperitoneal injection at doses of 0.9, 1.8, and 3.6 mg elemental gallium per kg body weight for 21 days in one study and at 3.5 mg/kg for 33 days in a second study. All the gallium-treated rats gained weight. Rats given gallium at doses of 3.5 mg/kg or more grew at a lower rate than untreated controls (-7 and -10% at doses of 3.5 and 3.6 mg/kg, respectively; p &lt; 0.05). At a dose of 0.9 mg/kg, gallium did not inhibit bone resorption or lower serum calcium but inhibited bone formation by 32% and bone apposition by 36% at the endosteal surface of the tibia. At a dose of 1.8 mg/kg, gallium produced modest hypocalcemia, prevented a rise in circulating 1,25-dihydroxyvitamin D [1,25-(OH)2D], inhibited bone resorption in implants, and inhibited bone formation by 19% and bone apposition by 18%. At a dose of 3.5 mg/kg, gallium lowered the serum calcium and serum 1,25-(OH)2D, inhibited growth, and accentuated the antiresorptive and antiformative effects seen at the two lower doses. The results indicate that gallium inhibits bone resorption, produces hypocalcemia, alters vitamin D metabolism, and inhibits bone formation at doses below those that inhibit bone resorption. The mechanism for hypocalcemia may be by direct action on bone and could involve an indirect effect on calcium metabolism mediated by changes in the metabolism of vitamin D.

AbstractThe effects of prostaglandin E2 (PGE2) given in controlled-release pellets or by daily sc injection for 21 days on mineral homeostasis and bone histomorphometry were compared in 7-week-old female rats. Sham operation and ovariectomy were performed at the beginning of the studies. In experiment 1, 7.5 mg PGE2 or drug-free, controlled-release pellets were implanted sc at the back of the neck on day 7. In experiment 2, 3 mg/kg body weight of PGE2 or vehicle was injected sc daily beginning on day 7. The animals were sacrificed on day 28 of the two experiments, and the tibiae were removed for histomorphometric analysis of the diaphysis and metaphysis. When administered by pellets in experiment 1, PGE2 lowered serum 1,25-dihydroxyvitamin D and did not influence weight gain, serum calcium, phosphorus, or magnesium, cross-sectional or medullary areas, periosteal bone formation and apposition rates, endosteal bone formation and apposition rates, or endosteal tetracycline-labeled perimeter. PGE2 lowered cancellous bone area and cancellous bone perimeter in both the sham-operated and ovariectomized rats. In contrast, when administered by sc injection in experiment 2, PGE2 reduced weight gain, increased serum magnesium, increased cortical area, and reduced medullary area without changing cross-sectional area, increased periosteal bone formation and apposition rates and endosteal bone and apposition rates, did not alter endosteal tetracycline-labeled perimeter, and increased cancellous bone area and cancellous bone perimeter in both sham-operated and ovariectomized animals. PGE2 produced local inflammation when given by pellets, and the serum concentration of 13,14-dihydro-15-ketoprostaglandin E2, the major metabolite of PGE2, increased when PGE2 was given by sc injection but not when administered by pellets. Thus, PGE2 given sc by controlled-release pellets (1) produces local inflammation and systemic bone loss without increasing PGE2 systemically and (2) provides a model for inflammation-induced loss of cancellous bone. The results also indicate that the pellet is not a valid means for the delivery of PGE2 to the general circulation.