Lassa-VSV chimeric virus targets and destroys human and mouse ovarian cancer by direct oncolytic action and by initiating an anti-tumor response.

Ovarian cancer is the third most common female cancer, with poor survival in later stages of metastatic spread. We test a chimeric virus consisting of genes from Lassa and vesicular stomatitis viruses, LASV-VSV; the native VSV glycoprotein is replaced by the Lassa glycoprotein, greatly reducing neurotropism. Human ovarian cancer cells in immunocompromised nude mice were lethal in controls. Chemotherapeutic paclitaxel and cisplatin showed modest cancer inhibition and survival extension. In contrast, a single intraperitoneal injection of LASV-VSV selectively infected and killed ovarian cancer cells, generating long-term survival. Mice with human ovarian cancer cells in brain showed rapid deterioration; LASV-VSV microinjection into brain blocked cancer growth, and generated long-term survival. Treatment of immunocompetent mice with infected mouse ovarian cancer cells blocked growth of non-infected ovarian cancer cells peritoneally and in brain. These results suggest LASV-VSV is a viable candidate for further study and may be of use in the treatment of ovarian cancer.

Impact of food security on glycemic control among low-income primarily Hispanic/Latino children in Los Angeles, California: A cross-sectional study.

Studies examining the impact of food insecurity on metabolic markers are limited, specifically in Hispanic youth. This study was a cross-sectional analysis of 218 3rd-5th grade students (83% Hispanic and 49% male). Anthropometrics, blood glucose, insulin, and lipids via fasting blood draw, dietary intake via Block screener, and a 5-item food security scale were collected. HOMA-Insulin Resistance was calculated. Multivariate analyses of covariance were used to examine differences in glucose and insulin indices, adiposity, metabolic and dietary intake variables between categories of food security. Food secure children had greater glycemic control and decreased insulin resistance compared to food insecure children.

Validity and Reliability of an Expanded Vegetable Questionnaire Among Elementary School Children.

BACKGROUND: The purpose of this study was to expand the School Physical Activity and Nutrition questionnaire to include a greater variety of vegetables and to evaluate the relative validity and reliability of these revised items. OBJECTIVES: This study utilized 2 convenience samples of third to fifth graders for an analysis: validity (n = 70) and reliability (n = 76). Validity was assessed by comparing questionnaire items with vegetable intake reported from a 24-hour dietary recall covering the same reference period. Reliability estimates were assessed via same-day test-retest. RESULTS: Agreement correlations ranged from 0.35 to 0.71. Kappa statistics varied from 0.16 to 0.66. Percentage agreements ranged from 57% to 87%. Test-retest Spearman coefficients were greater than 0.50 for 6 items, weighted Kappa values were greater than 0.40 for all 7 items, and percentage agreement exceeded 75% for 5 items. CONCLUSIONS: Results suggest that the questionnaire is a valid and reliable measure of the previous day's vegetable intake in third- to fifth-grade students. This trial was registered at ClinicalTrials.gov as NCT02668744.

Consumption of artificial sweetened beverages associated with adiposity and increasing HbA1c in Hispanic youth.

Research examining the impact of artificial sweetened beverages (ASBs) on obesity and metabolic diseases in adolescents is limited. The overall goal is to examine the longitudinal effects of ASBs on changes in adiposity and metabolic parameters in Hispanic adolescents. Longitudinal cohort with 98 Hispanics (12-18 years) who were overweight or had obesity with the following data at baseline and 1-year later: anthropometrics, diet (24-h recalls), body composition (DXA), glucose and insulin dynamics (oral glucose tolerance and frequently sampled intravenous glucose tolerance test) and fasting lipids. Repeated measures analyses of covariance assessed changes over time between control (no ASBs at either visit), ASB initiators (no ASBs at baseline/ASBs at 1-year) and chronic ASB consumers (ASBs at both visits). ASB initiators (n = 14) and chronic ASB consumers (n = 9) compared to control (n = 75) had higher total body fat at baseline and 1-year (P = 0.05 for group effect). Chronic ASB consumers had a 6% increase in haemoglobin A1c, 34% increase in energy intake (kcal d-1 ) and 39% increase in carbohydrate intake (g d-1 ) over time, while control and ASB initiators maintained (P < 0.05 for group-by-time interactions). These results do not support promoting ASBs as a strategy for adiposity loss or to improve metabolic health.

LA sprouts randomized controlled nutrition, cooking and gardening programme reduces obesity and metabolic risk in Hispanic/Latino youth.

BACKGROUND: Many programmes for children that involve gardening and nutrition components exist; however, none include experimental designs allowing more rigorous evaluation of their impact on obesity. OBJECTIVES: The objective of this study is to explore the effects of a novel 12-week gardening, nutrition and cooking intervention {'LA Sprouts'} on dietary intake, obesity parameters and metabolic disease risk among low-income, primarily Hispanic/Latino youth in Los Angeles.. METHODS: This study used a randomized control trial involving four elementary schools [two randomized to intervention {172, 3rd-5th grade students}; two randomized to control {147, 3rd-5th grade students}]. Classes were taught in 90-min sessions once per week for 12 weeks. Data collected at pre-intervention and post-intervention included dietary intake via food frequency questionnaire, anthropometric measures {body mass index, waist circumference}, body fat, and fasting blood samples. RESULTS: LA Sprouts participants compared with controls had significantly greater reductions in body mass index z-scores {-0.1 vs. -0.04, respectively; p = 0.01} and waist circumference {-1.2 vs. 0.1 cm; p < 0.001}. Fewer LA Sprouts participants had the metabolic syndrome after the intervention than before, while controls with metabolic syndrome increased. LA Sprouts participants compared with controls increased dietary fiber intake {+3.4% vs. -16.5%; p = 0.04}. All participants decreased vegetable intake, but decreases were less in LA Sprouts than controls {-3.7% vs. -26.1%; p = 0.04}. Change in fruit intake did not differ between LA Sprouts and controls. CONCLUSIONS: LA Sprouts was effective in reducing obesity and metabolic risk; however, additional larger and longer-term studies are warranted.

Associations among sugar sweetened beverage intake, visceral fat, and cortisol awakening response in minority youth.

CONTEXT: Abdominal adiposity has long been associated with excess caloric intake possibly resulting from increased psychosocial stress and associated cortisol dysfunction. However, the relationship of sugar-sweetened beverage (SSB) intake specifically with cortisol variability and visceral adipose tissue (VAT) is unknown. OBJECTIVE: To examine the relationships between SSB intake, VAT, and cortisol response in minority youth. DESIGN: A cross-sectional analysis. SETTING: The University of Southern California. PARTICIPANTS: 60 overweight/obese Non-Hispanic Black and Hispanic adolescents ages 14-18years. MAIN OUTCOME MEASURES: VAT via Magnet Resonance Imaging (MRI), cortisol awakening response (CAR) via multiple salivary samples, and SSB intake via multiple 24-hour diet recalls. SSB intake was divided into the following: low SSB consumers (<1 servings per day), medium SSB consumers (≥1-<2 servings per day), high SSB consumers (≥2 servings per day). Analysis of covariance were run with VAT and CAR as dependent variables and SSB intake categories (independent variable) with the following a priori covariates: sex, Tanner stage, ethnicity, caloric intake, and body mass index. RESULTS: The high SSB intake group exhibited a 7% higher VAT compared to the low SSB intake group (ß=0.25, CI:(0.03, 0.33), p=0.02). CAR was associated with VAT (ß=0.31, CI:(0.01,0.23), p=0.02). The high SSB intake group exhibited 22% higher CAR compared to the low SSB intake group (ß=0.30, CI:(0.02,0.48), p=0.04). CONCLUSION: This is the first study exploring the relationship between SSB, VAT, and CAR. SSB consumption appears to be independently associated greater abdominal adiposity and higher morning cortisol variability in overweight and obese minority youth. This study highlights potential targets for interventions specifically to reduce SSB intake in a minority youth population.

Dietary fibre linked to decreased inflammation in overweight minority youth.

OBJECTIVE: The objective of this study was to examine the relationship between diet and inflammation, and adiposity in minority youth. DESIGN AND METHODS: The study was designed as a cross-sectional analysis of 142 overweight (≥85th body mass index percentile) Hispanic and African-American adolescents (14-18 years) with the following measures: anthropometrics, adiposity via magnetic resonance imaging, dietary intake via 24-h dietary recalls, and inflammation markers from fasting blood draws utilizing a multiplex panel. Partial correlations were estimated and analysis of covariance (ancova) models fit to examine the relationship among dietary variables, inflammation markers and adiposity measures with the following a priori covariates: Tanner stage, ethnicity, sex, total energy intake, total body fat and total lean mass. RESULTS: Inference based on ancova models showed that the highest tertile of fibre intake (mean intake of 21.3 ± 6.1 g d(-1) ) vs. the lowest tertile of fibre intake (mean intake of 7.4 ± 1.8 g d(-1) ) was associated with 36% lower plasminogen activator inhibitor-1 (P = 0.02) and 43% lower resistin (P = 0.02), independent of covariates. Similar results were seen for insoluble fibre. No other dietary variables included in this study were associated with inflammation markers. CONCLUSIONS: These results suggest that increases in dietary fibre could play an important role in lowering inflammation and therefore metabolic disease risk in high-risk minority youth.

Association of gestational diabetes and breastfeeding on obesity prevalence in predominately Hispanic low-income youth.

OBJECTIVE: The goal of this study was to examine if breastfeeding duration by gestational diabetes mellitus status impacted the prevalence of obesity in offspring. METHODS: Data were obtained from a 2011 phone survey with caregivers of low-income children (2-4 years) participating in the Women, Infants and Children programme in Los Angeles County. The final sample included 2295 children, 84% Hispanic and 48% female. Chi-square and binary logistic regression were used to assess gestational diabetes status and breastfeeding duration on the prevalence of obesity, with the following a priori covariates: child's ethnicity, birth weight, age in months and sex. RESULTS: Breastfeeding and gestational diabetes were significantly associated with obesity prevalence (P < 0.01). Using gestational diabetes mellitus and no breastfeeding as the referent category, gestational diabetes mellitus offspring who were breastfed ≥12 months had a 72% decrease in obesity prevalence (adjusted odds ratio = 0.28, confidence interval 0.89-0.03, P = 0.05). CONCLUSIONS: These findings suggest that > 12 months of breastfeeding duration in the gestational diabetes mellitus group and any duration of breastfeeding in the non-gestational diabetes mellitus mothers is needed to reduce obesity levels in a primarily Hispanic population.

Increased eating frequency linked to decreased obesity and improved metabolic outcomes.

BACKGROUND: We previously reported that more frequent eating in overweight minority youth was linked to lower visceral adiposity and circulating triglycerides. The aim of this study was to examine this issue in more detail by assessing the relationship between eating frequency and adiposity and metabolic disease risk in a cohort of exclusively overweight Hispanic youth. METHODS: This analysis included 191 overweight (⩾ 85th percentile body mass index (BMI)) Hispanic youth (8-18 years) with the following cross-sectional measures: height, weight, BMI, dietary intake via multiple 24 h recalls, body composition via dual-energy X-ray absorptiometry, lipids and insulin action (insulin sensitivity, acute insulin response (AIR) and disposition index, a measure of ß-cell function) via a frequently sampled intravenous glucose tolerance test. Each eating occasion (EO) was defined as ⩾ 50 calories and ⩾ 15 min from any prior EO. Infrequent eaters (IEs) were classified as any subject who ate <3 EOs on any dietary recall (n = 32), whereas frequent eaters (FEs) always consumed ⩾ 3 EOs (n = 159). RESULTS: Using analyses of covariance, FEs compared with IEs consumed 23% more calories per day (P ⩽ 0.01), ate 40% more often and consumed 19% less calories per EO (P ⩽ 0.01). FEs also exhibited 9% lower BMI Z-scores (P ⩽ 0.01), 9% lower waist circumferences (P ⩽ 0.01), 29% lower fasting insulin (P = 0.02), 31% lower HOMA-IR (Homeostatic Model Assessment: Insulin Resistance) values (P = 0.02) and 19% lower triglycerides (P ⩽ 0.01), as well as an 11% higher AIR (P = 0.02) and 31% higher disposition index (P=0.01). The following a priori covariates were included: Tanner, sex, body fat and reported energy intake. CONCLUSION: These findings suggest that increased eating frequency is related to decreased obesity and metabolic disease risk in overweight Hispanic youth, despite increases in energy intake.

Compensatory responses to insulin resistance in obese African-American and Latina girls.

PURPOSE: Insulin responses to oral and intravenous glucose markedly differ by ethnicity. This study examined whether ethnic differences in pancreatic insulin secretion, hepatic insulin extraction and clearance explain these disparate findings in 35 obese African-American and 41 Latina girls (Tanner Stages: IV-V; ages: 14-18; body mass index percentile: 85.9-99.8%). METHODS: Pancreatic insulin secretion, hepatic insulin extraction and clearance were estimated by C-peptide and insulin modeling during an oral glucose tolerance test. Insulin sensitivity (SI), acute insulin response to glucose (AIRG ) and disposition index were derived from a frequently sampled intravenous glucose tolerance test. RESULTS: Compared to Latinas, obese African-American adolescents had lower pancreatic insulin secretion (21.3%; P < 0.01), glucose incremental area under the curve (IAUC) (41.7%, P = 0.02), C-peptide IAUC (25.1%, P < 0.01) and SI (33.7%; P < 0.01). There were no ethnic differences in hepatic insulin extraction and clearance (P's > 0.05). CONCLUSIONS: Compensatory mechanisms to insulin resistance do not appear to explain the ethnic differences in insulin responses to oral and intravenous glucose in obese African-American and Latina girls.

Effects of a randomized maintenance intervention on adiposity and metabolic risk factors in overweight minority adolescents.

OBJECTIVE: The objective of this study was to assess the effects of a maintenance programme (monthly newsletters vs. monthly group classes and telephone behavioural sessions) on obesity and metabolic disease risk at 1 year in overweight minority adolescents. METHODS: After a 4-month nutrition and strength training intervention, 53 overweight Latino and African-American adolescents (15.4 ± 1.1 years) were randomized into one of two maintenance groups for 8 months: monthly newsletters (n = 23) or group classes (n = 30; monthly classes + individualized behavioural telephone sessions). The following outcomes were measured at months 4 (immediately following the intense intervention) and 12: height, weight, blood pressure, body composition via BodPod™ (Life Measurement Instruments, Concord, CA, USA), lipids and glucose/insulin indices via frequently sampled intravenous glucose tolerance test. RESULTS: There were no significant group by time interactions for any of the health outcomes. There were significant time effects in several outcomes for both groups from months 4 to 12: bench press and leg press decreased by 5% and 14%, respectively (P = 0.004 & P = 0.01), fasting insulin and acute insulin response decreased by 26% and 16%, respectively (P < 0.001 & P = 0.046); while high-density lipoprotein cholesterol and insulin sensitivity improved by 5% and 14% (P = 0.042 & P = 0.039). CONCLUSIONS: Newsletters as opposed to group classes may suffice as follow-up maintenance programmes to decrease type 2 diabetes and cardiovascular risk in overweight minority adolescents.

Influence of elevated liver fat on circulating adipocytokines and insulin resistance in obese Hispanic adolescents.

OBJECTIVE: We performed this study to examine the metabolic differences arising from higher liver fat accumulation in obese Hispanic adolescents, with a particular focus on circulating levels of adipocytokines and insulin resistance. METHODS: Forty-one obese Hispanic adolescents (15.3 ± 1.0 years, body mass index percentile: 97.0 ± 3.9) were assessed for: visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and hepatic fat fraction (HFF) by magnetic resonance imaging; fasting measures of serum glucose, insulin and adipocytokines; homeostasis model assessment of insulin resistance (HOMA-IR); and insulin sensitivity (SI) and the acute insulin response to glucose (AIR) by intravenous glucose tolerance test. Subjects with normal levels of HFF (below 5%; n = 25) were compared to those with HFF > 5% (n = 16). RESULTS: The two groups differing in HFF were similar for total body fat, VAT and SAT. The group with HFF > 5% had significantly (P < 0.05) higher interleukin-8 (IL-8) (6.1 ± 1.6 vs. 3.2 ± 0.4 pg mL(-1) ), NGF (30.2 ± 9.9 vs. 13.9 ± 1.6 pg mL(-1) ), HOMA-IR (8.8 ± 1.1 vs. 5.5 ± 0.5), AIR (1869 ± 206 vs. 1092 ± 165) and a tendency for lower SI (1.2 ± 0.4 vs. 2.1 ± 0.3; P = 0.06), with no significant differences in any of other factors measured. CONCLUSIONS: These data suggest that elevated liver fat is most closely associated with elevated serum IL-8 and NGF levels as well as increased AIR and HOMA-IR. These elevated factors may play significant roles in the metabolic abnormalities associated with elevated liver fat in obese Hispanics.

Adiponectin and leptin are independently associated with insulin sensitivity, but not with insulin secretion or beta-cell function in overweight Hispanic adolescents.

The aim of the study was to investigate the independent effects of leptin and adiponectin on insulin sensitivity as well as insulin secretion and beta-cell function in overweight Hispanic adolescents. Despite pubertal changes in hormone secretion, studies investigating the independent effect of both hormones on insulin sensitivity and beta-cell function in adolescents are lacking. In a cross-sectional study, 175 overweight Hispanic adolescent boys (n=101) and girls (n=74) with a family history of diabetes were recruited and insulin sensitivity (SI), acute insulin response to glucose (AIR), disposition index (DI), body composition, total serum adiponectin, and leptin were assessed. Over age, leptin significantly increased in girls but not in boys (p for age x gender interaction=0.005) while adiponectin was similar in boys and girls. Leptin was not correlated to adiponectin. Leptin (partial r=-0.180; p=0.019) and adiponectin (partial r=0.230; p=0.003) predicted SI independent of age, gender, body fat, lean body mass, and Tanner stage but together, they explained 5% of the unique variation in SI (p for R (2)-change<0.001). Leptin or adiponectin were not related to AIR or DI. With regard to SI, AIR, and DI, no significant gender, age, or Tanner stage interactions were observed suggesting similar effects of adiponectin and leptin among gender, age, and Tanner stages. Leptin and adiponectin were independently associated with SI, but not with insulin secretion or beta-cell function.

Combined association of maternal and paternal family history of diabetes with plasma leptin and adiponectin in overweight Hispanic children.

AIMS: To investigate the importance of a maternal and paternal family history of Type 2 diabetes and their combined association with plasma leptin and adiponectin levels in overweight Latino children with a family history of Type 2 diabetes (T2DM). METHODS: This cross-sectional study investigated the combined association of a maternal and paternal family history of T2DM with leptin and adiponectin in 175 overweight Latino children (age 11.1 +/- 1.7 years). All subjects had a family history of T2DM. Plasma adiponectin and leptin levels, body fat measured by dual-energy X-ray absorptiometry, Tanner stage, age and insulin sensitivity were assessed. RESULTS: After adjustment for age, gestational diabetes, insulin sensitivity and body fat, a combined maternal and paternal family history of T2DM was associated with higher leptin concentrations (P = 0.004) compared with a maternal or paternal family history alone. This association was most pronounced at Tanner stage 1 (P for interaction family history x tanner stage = 0.022). The presence of a combined maternal and paternal family history of T2DM accounted for 4% (P = 0.003) of the variation in leptin concentrations. No such combined association was observed for adiponectin levels. CONCLUSIONS: Maternal and paternal family history of T2DM may have an additive impact on leptin, but not on adiponectin levels independent of adiposity and insulin sensitivity in overweight Latino children. This may contribute to a further clinically relevant deterioration of metabolic health in this population.

Leptin-to-adiponectin ratio as independent predictor of insulin sensitivity during growth in overweight Hispanic youth.

Because leptin and adiponectin are counter-regulated in vivo and exert opposing effects on glucose metabolism, fat oxidation and insulin sensitivity, the ratio of leptin-to-adiponectin has been investigated as a potential atherogenic index, suggesting that the index is a better biomarker for atherosclerotic risk in obese Type 2 diabetic patients than either leptin or adiponectin alone. However, no information is available regarding the leptin-to-adiponectin ratio during adolescence in Hispanic adolescents. Therefore, the present study was designed to investigate the leptin-to-adiponectin ratio during growth and to establish whether the leptin-to-adiponectin ratio is a better predictor for insulin sensitivity compared to leptin and adiponectin alone in a regression model. From the age of 8 to 14, the leptin-to-adiponectin ratio increased from 2.0+/-0.8 to 5.8+/-2.2 in girls, with no significant change noted in boys (gender x age interaction p=0.007). In a multiple regression analysis, including both adiponectin and leptin as independent variables, leptin and adiponectin explained 5% of the variation in insulin sensitivity independent of gender, age, Tanner stage, total fat mass and lean body mass (p for R2-change <0.001). The leptin-to-adiponectin ratio also explained 5% of the variation in insulin sensitivity, after controlling for the same covariates (p for R2-change <0.001). These data indicate that the leptin-to-adiponectin ratio is not a better predictor of insulin sensitivity during growth than the additive effects of leptin and adiponectin levels.

Differences in the corticospinal projection from primary motor cortex and supplementary motor area to macaque upper limb motoneurons: an anatomical and electrophysiological study.

To further our understanding of the functional roles of different motor cortical areas, we made a quantitative comparison of the density of corticospinal projections from primary motor cortex (M1) and supplementary motor area (SMA) to spinal motor nuclei supplying hand and finger muscles in four macaque monkeys. We also compared the action of corticospinal outputs excited by electrical stimulation of these two areas on upper limb motoneurons recorded in three anaesthetized macaques. The hand representations of SMA and M1 were first identified using structural magnetic resonance imaging scans and intracortical microstimulation. In the anatomical study we then made focal injections of wheatgerm agglutinin- horseradish peroxidase into these representations, which were subsequently confirmed by analysis of retrograde cortical labelling. Densitometric analysis showed that corticospinal projections from M1 were denser and occupied a greater proportion of the hand muscle motor nuclei than did projections from SMA. In caudal Th1 the densest projections from M1 occupied 81% of this motoneuronal area, compared with only 6% from SMA. In the electrophysiological study, bipolar intracortical stimulation of the hand representation of M1 and SMA evoked direct (D) and indirect (I) corticospinal volleys. Volleys elicited by M1 stimulation had larger amplitudes and faster conduction velocities than those evoked from the SMA. Intracellular recordings were made from 84 contralateral upper limb motoneurons. M1 and SMA stimulation evoked markedly different responses in tested motoneurons: EPSPs were larger and more common from M1 (88% of motoneurons) than from SMA (48%). Some motoneurons (16/84) showed evidence of excitatory postsynaptic potentials mediated by monosynaptic action of the D-wave evoked from M1; these early effects were not observed from the SMA. In most motoneurons (74/84) EPSPs had segmental latencies indicating that they were due to monosynaptic action of the I-wave. The results are consistent with cortico-motoneuronal (CM) connections originating from both SMA and M1 converging upon single motoneurons, but those from M1 are far more numerous and exert stronger excitatory effects than from the SMA. Thus although they may function in parallel, the two CM projections probably make different contributions to upper limb motor control.

Phosphatidylinositol-4-phosphate 5-kinase-1beta is essential for epidermal growth factor receptor-mediated endocytosis.

Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is known to play an important role in signal transduction and membrane trafficking. We show that one enzyme responsible for PIP(2) production, phosphatidylinositol-4-phosphate 5-kinase type 1beta (PIPKbeta), is essential for epidermal growth factor receptor (EGFR)-mediated endocytosis. Expression of murine PIPKbeta in NR6 cells expressing EGFR strikingly increased receptor internalization. Moreover, the kinase was shown to form an immunoprecipitable complex with EGFR. Expression of either a truncated kinase or a kinase dead mutant inhibited EGFR endocytosis and also blocked the membrane recruitment of PIPKbeta and both clathrin light chain and dynamin. Our results delineate a novel mechanism by which PIPKbeta regulates receptor-mediated endocytosis and receptor tyrosine kinase membrane traffic.

Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass.

BACKGROUND: The bioactive peptide endothelin-1 is elevated during and after cardiopulmonary bypass and exerts cardiovascular effects through its 2 receptor subtypes, endothelin-1A and endothelin-1B. Increased endothelin-1A receptor stimulation after cardiopulmonary bypass can cause increased pulmonary vascular resistance and modulate myocardial contractility. However, whether and to what degree selective endothelin-1A blockade influences these parameters in the postbypass setting is not completely understood. OBJECTIVES: Our objective was to measure left ventricular function and hemodynamics in a porcine model of cardiopulmonary bypass after selective blockade of endothelin-1A. METHODS: Adult pigs (n = 23) underwent 90 minutes of cardiopulmonary bypass and were randomized 30 minutes after bypass to receive a selective endothelin-1A antagonist (TBC 11251, 10 mg/kg; n = 13) or saline vehicle (n = 10). RESULTS: After bypass and before randomization, pulmonary vascular resistance rose nearly 4-fold, and left ventricular preload recruitable stroke work fell to one third of baseline values (both P <.05). In the vehicle group pulmonary vascular resistance continued to rise, and preload recruitable stroke work remained reduced. However, after endothelin-1A blockade, the rise in pulmonary vascular resistance was significantly blunted compared with that in the vehicle group. Moreover, the reduction in pulmonary vascular resistance with endothelin-1A blockade was achieved without a significant change in systemic perfusion pressures. CONCLUSIONS: The present study demonstrated that increased activity of the endothelin-1A receptor likely contributes to alterations in pulmonary vascular resistance in the postbypass setting. Selective endothelin-1A blockade may provide a means to selectively decrease pulmonary vascular resistance without significant effects on systemic hemodynamics.

Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.

The enzyme protein farnesyltransferase, which catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first farnesyltransferase inhibitors to undergo clinical testing. In the present study, we examined the effect of combining SCH66336 with several classes of antineoplastic drugs in various human tumor cell lines. Flow cytometry indicated that SCH66336 had no effect on the cell cycle distribution of treated cells. Nonetheless, colony-forming assays revealed that the antiproliferative effects of SCH66336 and 5-fluorouracil were less than additive. In contrast, the effects of SCH66336 and melphalan were additive. Moreover, the combination of SCH66336 + cisplatin produced antiproliferative effects that were additive or synergistic over a broad range of clinically achievable concentrations in A549 non-small cell lung cancer cells and T98G human glioblastoma cells, but less than additive in MCF-7 breast, HCT116 colon, or BxPC-3 pancreatic adenocarcinoma cells. Examination of the effect of drug sequencing in A549 cells revealed synergism when cells were exposed to SCH66336 and then cisplatin and antagonism when drugs were administered in the opposite order. The additive and synergistic effects resulted in enhanced apoptosis with the SCH66336 + cisplatin combination. Additional studies failed to show any effect of SCH66336 on the formation or removal of platinum-DNA adducts, raising the possibility that SCH66336 is affecting survival of cisplatin-treated cells downstream of the DNA lesions. These observations suggest that SCH66336 exhibits additive or synergistic effects when combined with cisplatin in a sequence- and cell line-dependent fashion. Additional preclinical and clinical study of this combination appears warranted.

Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes.

Dietary intake of soy has been associated with a decreased risk of cancer. Soy isoflavones have been postulated to be the protective compounds in soybeans; however, the precise mechanism by which soy isoflavones prevent human cancer is not known. The major soy isoflavones, genistein and daidzein, are antioxidant compounds, therefore one possible mechanism of action is through their antioxidant effect. We have previously demonstrated that the soy isoflavone, genistein, inhibits the activation of the redox-sensitive transcription factor, NF-kappa B, in prostate cancer cells in vitro. In this study, we have demonstrated that genistein, but not daidzein, inhibits TNF-alpha-induced NF-kappa B activation in cultured human lymphocytes. Additionally, we investigated the in vivo effect of soy isoflavone supplementation on NF-kappa B activation induced by TNF-alpha in vitro in peripheral blood lymphocytes of six healthy men. We show that healthy male subjects receiving 50 mg isoflavone mixture (Novasoy) twice daily for 3 weeks are protected from TNF-alpha induced NF-kappa B activation. Additionally, we observed a reduction of 5-hydroxymethyl-2'-deoxyuridine (5-OHmdU), a marker for oxidative DNA damage, following isoflavone supplementation. The inhibitory effect of soy isoflavones was no longer present 3 months after the supplementation. This preliminary study demonstrates that soy isoflavone supplementation may protect cells from oxidative stress-inducing agents by inhibiting NF-kappa B activation and decreasing DNA adduct levels.