Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non–Small Cell Lung Cancer

Introduction

Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)–receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656).

Dosimetry of radioiodine therapy in patients with nodular goiter after pretreatment with a single, low dose of recombinant human thyroid-stimulating hormone.

A single, low dose of recombinant human thyroid-stimulating hormone (rhTSH) doubles 24-h RAIU and causes a more homogeneous distribution of radioiodine on thyroid scintigrams of patients with nodular goiter. Pretreatment with rhTSH allows the therapeutic dose of (131)I to be reduced by 50%-60% without compromising the result of thyroid volume reduction. The present study focused on the dosimetric aspects of therapy with a reduced dose of (131)I after pretreatment with rhTSH in patients with nodular goiter. METHODS: Thirty-six patients were treated with (131)I to reduce thyroid volume. Nine patients were pretreated with a single dose of 0.01 mg of rhTSH, and 9 patients, with 0.03 mg of rhTSH. Two control groups of 9 patients, matched for thyroid weight and 24-h radioactive iodide uptake, were not pretreated with rhTSH. The therapeutic dose of (131)I was aimed at being sufficient to result in retention of 3.7 MBq of (131)I per gram of thyroid tissue at 24 h. Thyroid radioactivity after (131)I administration was measured every 24 h for 3 d and on days 7, 10, 14, 21, and 28. A model of iodine biokinetics was used to estimate absorbed doses in organs. Protein-bound (131)I activity was measured at 1, 2, 3, 7, and 10 d and at 2, 3, and 4 wk after (131)I therapy. RESULTS: The administered activities were 1.5 times lower in the 0.01-mg rhTSH group and 1.9 times lower in the 0.03-mg rhTSH group than in the control groups. The absorbed dose in the thyroid was similar in the rhTSH-pretreated groups and in the control groups. In the organs of excretion (bladder) and uptake (stomach) of inorganic iodide, the absorbed doses were 2- to 3-fold lower in the pretreated groups than in the control groups. The effective dose equivalent outside the thyroid was considerably lower in the rhTSH-pretreated groups than in their respective control groups (1.6-fold in the 0.01-mg rhTSH group and 2.3-fold in the 0.03-mg rhTSH group). The time course of protein-bound (131)I activity in serum and the cumulated protein-bound (131)I activity in serum did not differ significantly between rhTSH-pretreated and control groups. CONCLUSION: (131)I therapy after pretreatment with a single, low dose of rhTSH, with the dose reduced according to the rhTSH-induced increase in 24-h radioactive iodide uptake, caused lower radiation-absorbed doses in extrathyroidal organs and tissues, especially bladder and stomach, and no significant increase in the release of (131)I-labeled thyroid hormones into the circulation of patients with nodular goiter. Thus, this mode of therapy can be recommended, especially when the dose of radioiodine to be administered without rhTSH pretreatment is high.     

The dutch national clinical audit for lung cancer: A tool to improve clinical practice? An analysis of unforeseen ipsilateral mediastinal lymph node involvement in the Dutch Lung Surgery Audit (DLSA)

Objective

Optimal treatment selection for patients with non-small cell lung cancer (NSCLC) depends on the clinical stage of the disease. Particularly patients with mediastinal lymph node involvement (stage IIIA-N2) should be identified since they generally do not benefit from upfront surgery. Although the standardized preoperative use of PET-CT, EUS/EBUS and/or mediastinoscopy identifies most patients with mediastinal lymph node metastasis, a proportion of these patients is only diagnosed after surgery. The objective of this study was to identify all patients with unforeseen N2 disease after surgical resection for NSCLC in a large nationwide database and to evaluate the preoperative clinical staging process.

Feeding Rats Diets Enriched in Lowbush Blueberries for Six Weeks Decreases Ischemia-induced Brain Damage

Abstract

Oxidative stress is an important element in the etiology of ischemic stroke. Lowbush blueberries (Vaccinium angustifolium Aiton) have a high antioxidant capacity and thus we determined whether consumption of lowbush blueberries would protect neurons from stroke-induced damage. Rats were fed AIN-93G diets containing 0 or 14.3% blueberries (g fresh weight/100 g feed) for 6 weeks. Stroke was then simulated by ligation of the left common carotid artery (ischemia), followed by hypoxia. One week later, plasma and urine were collected, and neuronal damage in the hippocampus was determined histologically. In control rats, hypoxia-ischemia resulted in 40±2% loss of neurons in the hippocampus of the left cerebral hemisphere, as compared to the right hemisphere. Rats on blueberry-supplemented diets lost only 17±2% of neurons in the ischemic hippocampus. Neuroprotection was observed in the CA1 and CA2 regions, but not CA3 region, of the hippocampus. The blueberry diet had no detectable effects on the plasma or urine oxygen radical absorbance capacity (ORAC) or plasma lipids. We conclude that consumption of lowbush blueberries by rats confers protection to the brain against damage from ischemia, suggesting that inclusion of blueberries in the diet may improve ischemic stroke outcomes.     

Glutamine synthetase deficiency in murine astrocytes results in neonatal death

Glutamine synthetase (GS) is a key enzyme in the “glutamine‐glutamate cycle” between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS^fl/lacZ or GS^fl/fl mice with hGFAP‐Cre mice resulted in prenatal excision of the GS^fl allele in astrocytes. “GS‐KO/A” mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14‐fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6‐fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS‐KO/A mice. The temporal dissociation between GS^fl elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS‐deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine‐glutamate and the associated alanine‐lactate cycles. © 2010 Wiley‐Liss, Inc.     

Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA cohort

BACKGROUND: Toxicity is the most important reason for premature switching of highly active antiretroviral therapy (HAART). In order to optimize the benefit-risk ratio of HAART, guidelines for toxicity management are needed. OBJECTIVE: An observational cohort study to estimate the incidence and identify determinants of toxicity-driven switches on second-line HAART after having switched first-line HAART despite successful viral suppression. METHODS: Patients were selected from those in the ATHENA cohort (n = 2470) who switched the initial HIV protease inhibitor (PI)-containing HAART while plasma HIV-1 RNA was 相似文献   

Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens

Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV.