Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter.

Background: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587).

Methods: Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days 1-5 of every 28-day cycle × 6)] or PBO + RT + TMZ following the same regimen.

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.

Background: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study.

Patients And Methods: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle.

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer.

Introduction: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC.

Methods: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1-14, in combination with pembrolizumab on day 1 of a 21-day cycle.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

Background: nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported.

Patients And Methods: Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).

Effects of birth weight and postnatal nutrition on neonatal sheep: III. Regulation of energy metabolism.

This study investigated effects of birth weight and postnatal nutrition on regulation of energy metabolism in the neonatal lamb. Low (mean +/- SD 2.289 +/- 0.

Maternal leptin is elevated during pregnancy in sheep.

Maternal plasma leptin is elevated during pregnancy in several species, but it is unclear to what extent this elevation reflects changes in adiposity or energy balance. Therefore, Karakul ewes (n = 8) were fed to minimize changes in maternal energy status over the pregnancy-lactation cycle. They were studied 20-40 d before breeding and during mid pregnancy (d 50-60 post coitus [PC]), late pregnancy (d 125-135 PC) and early lactation (d 15-22 post partum).

Influences on fetal and placental weights during mid to late gestation in prolific ewes well nourished throughout pregnancy.

This study investigated associations between fetal and placental weights from 85 to 130 days gestation in 49 fetuses from 21 ewes of a prolific genotype used as an experimental model of intrauterine growth retardation. The proportion of variation in fetal weight explained by placental weight increased from zero at 85 days to 91% (residual standard deviation (RSD) = 260 g) at 130 days. Overall, stage of pregnancy plus placental weight accounted for 96% of fetal weight variation (RSD = 212 g).

Development of a specific radioimmunoassay to measure physiological changes of circulating leptin in cattle and sheep.

Studies of leptin in large domestic ruminants have been limited to measurements of gene expression because methods to measure circulating levels are not available. To develop a bovine leptin radioimmunoassay, we produced recombinant bovine leptin and used it to immunize rabbits, and to prepare bovine leptin tracer and standards. A single antiserum with sufficient affinity and titer was identified.

An ultrasound-guided procedure to administer a label of DNA synthesis into fetal sheep.

A novel technique was developed to deliver a bolus dose of a DNA label into the peritoneal cavity of fetal sheep at 85-130 days gestation. Use of markers to identify the site of injection in fetuses from litters up to quadruplets, and immunohistochemistry to detect the DNA label, 5-bromo-2'-deoxyuridine (BrdU), confirmed the procedure was successful in 85% of cases. Duration of the procedure was (mean +/- SD) 44 +/- 16 min, and recovery from anaesthesia was rapid and uneventful in all cases.

Intrauterine growth retardation is associated with reduced cell cycle activity, but not myofibre number, in ovine fetal muscle.

Cellular development of muscle was studied in sheep fetuses at 85 days of gestation. Large and small fetuses were compared at 100, 115 and 130 days, and an additional group of large 130-day fetuses were studied following 7 days of maternal undernutrition. Myogenesis in the peroneus longus muscle was completed between 100 and 115 days of gestation, and myofibre number did not differ between small and large fetuses.

Protein requirements of sheep in late pregnancy: partitioning of nitrogen between gravid uterus and maternal tissues.

The objective of this study was to quantify effects of maternal protein nutrition on N accretion or loss in conceptus and maternal tissues of ewes during late pregnancy. Ewes, pregnant with twins, were fed low (LP, 79 g CP/kg DM), medium (MP, 116 g CP/kg DM), or high (HP, 157 g CP/kg DM) protein diets, each with an estimated ME concentration of 2.7 Mcal/kg DM, between d 111 and 140 of pregnancy; all ewes had been fed the same diet (2.

High-affinity neuropeptide Y receptor antagonists.

Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists.

Growth and accretion of energy and protein in the gravid uterus during late pregnancy in Holstein cows.

Multiparous Holstein cows (n = 18) were bred artificially to the same bull and then slaughtered at times ranging from 190 to 270 d postconception to assess accretion of energy, protein, fat, and ash by the conceptus. Wet weights, dry weights, and concentrations of energy, CP, crude fat, and ash were obtained for the following: fetus, combined amniotic and allantoic fluids, fetal membranes, cotyledons, caruncles, and uterine tissues. Rates of accumulation of these components in the gravid uterus (sum of all uterine contents) and fetus were described by linear or quadratic equations.

Pregnancy but not moderate undernutrition attenuates insulin suppression of fat mobilization in sheep.

Nonpregnant and late-pregnant ditocous ewes were fed either to maintain zero energy balance in maternal tissues (fed) or at 50% of this level (underfed) for several weeks. Plasma concentrations of nonesterified fatty acids (NEFA) and glycerol were measured under basal conditions and during infusion of various doses of insulin while maintaining euglycemia (hyperinsulinemic, euglycemic clamp technique). Pregnancy and undernutrition separately increased basal plasma NEFA concentration in an additive manner; plasma glycerol was increased by pregnancy but unaffected by undernutrition.

Relations between maternal and fetal plasma concentrations of placental lactogen and placental and fetal weights in well-fed ewes.

The concentration of ovine placental lactogen (oPL) in maternal plasma varies with litter size and nutritional status, making it difficult to compare these concentrations across studies. In this study, 27 Dorset and Finn-Dorset crossbred ewes with litters of known size and gestational age were used to relate concentrations of oPL in maternal plasma to placental and fetal weights. Fetal oPL concentrations also were correlated to these variables in 12 chronically catheterized singleton fetuses.

Chronic heat stress and prenatal development in sheep: I. Conceptus growth and maternal plasma hormones and metabolites.

Pregnant ewes were chronically exposed to thermoneutral (TN; 20 degrees C, 30% relative humidity) or hot (H; 40 degrees C 9 h/d, 30 degrees C 15 h/d, 40% relative humidity) environments between d 64 and 136 to 141 of pregnancy. They were sampled for blood at 14-d intervals during this period for measurement of plasma metabolites and hormones, then slaughtered and dissected to measure conceptus weights, dimensions and fetal organ weights. Rectal temperatures of H ewes were elevated .

Surgical cannulation of a hepatic vein in dairy cows utilizing diagnostic ultrasound.

Use of a diagnostic ultrasonography unit in the placement of hepatic vein catheters is described. Diagnostic ultrasound proved to be a safe and rapid means of identifying the hepatic venous circulation. It provided a clear visual guide in an otherwise blind surgical procedure and allowed for a precise determination of catheter placement.

Glucose absorption and hepatic gluconeogenesis in dairy cows fed diets varying in forage content.

One dry and four lactating Holstein cows were prepared with chronic catheters in the mesenteric, hepatic and portal veins and used to study glucose absorption and hepatic gluconeogenesis. The dry cow was used in a preliminary assessment of the methods. In the main experiment high concentrate and high forage diets, providing equal energy intake, were delivered in hourly portions from an automatic feeder as total mixed rations.

Control of nucleic acid and protein synthesis in developing brain, kidney, and heart of the neonatal rat: effects of alpha-difluoromethylornithine, a specific, irreversible inhibitor of ornithine decarboxylase.

Ornithine decarboxylase (ODC) and the polyamines are thought to play a role in maturation of mammalian tissues. Daily postnatal administration of alpha-difluoromethylornithine (DFMO, a specific inhibitor of ODC) to newborn rats caused organ-specific deficits in tissue weight gain, with brain and kidney as the major targets. Subnormal organ weights were associated with deficits in the levels of nucleic acids and proteins in the affected tissues, and examination of the synthetic rates of DNA ([3H]thymidine incorporation), RNA ([3H]uridine incorporation) and protein ([14C]leucine incorporation) confirmed that macromolecule synthesis was inhibited in DFMO-treated pups.

Obligatory role of thyroid hormones in development of peripheral sympathetic and central nervous system catecholaminergic neurons: effects of propylthiouracil-induced hypothyroidism on transmitter levels, turnover and release.

Thyroid status is thought to play a major role in establishing the time course of development of sympathetic nerve pathways. Hypothyroidism induced by perinatal administration of propylthiouracil to developing rats resulted in substantial deficits in cardiac norepinephrine levels that persisted into adulthood. This shortfall was not accompanied by compensatory receptor supersensitivity or by increased utilization of remaining transmitter.

Ornithine decarboxylase and polyamines in developing rat brain and heart: Effects of perinatal hypothyroidism.

Hypothyroidism induced by perinatal administration of propylthiouracil (PTU) had profound effects on growth of the heart, with major organ weight deficits persisting well beyond the termination of drug treatment. These effects were preceded by disruption of the developmental patterns of cardiac ornithine decarboxylase (ODC) and the polyamines, which are thought to be intracellular modulators of cellular maturation. Activity of cardiac ODC was depressed in the PTU-treated group and putrescine and spermidine levels were markedly subnormal.

Effects of alpha-fluoromethylhistidine (FMH), an irreversible inhibitor of histidine decarboxylase, on development of brain histamine and catecholamine systems in the neonatal rat.

Daily administration of FMH to neonatal rats produced long-lasting inhibition of histidine decarboxylase in hypothalamus and cerebral cortex and led to depletion of histamine in both brain regions. The onset of depletion was more rapid in cerebral cortex, a region in which non-neurotransmitter pools of histamine predominate in early postnatal life, appearing as early as postnatal day 3; depletion in the hypothalamus, a region rich in histaminergic neuronal projections, appeared later. No effects were seen on body or brain growth, nor was development of other biogenic amine systems affected.

Critical periods for the role of ornithine decarboxylase and the polyamines in growth and development of the rat: Effects of exposure to α-difluoromethylornithine during discrete prenatal or postnatal intervals.

The roles of ornithine decarboxylase (ODC) and the polyamines in fetal and neonatal development were examined through the use of α-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ODC. Administration to pregnant rats of 500 mg/kg of DFMO every 12 h for a 4-day period (8 DFMO injections) resulted in fetal and neonatal death; DFMO early in gestation produced fetal resorption whereas late gestational exposure did not compromise fetal viability but instead resulted in a delayed toxic effect, with high mortality in the first postnatal week. Generalized toxicity of DFMO was not apparent in later developmental periods, as 4 days of DFMO treatment begun postnatally did not produce any neonatal death.