Molecular Subtyping of Invasive Breast Cancer Using a PAM50-Based Multigene Expression Test-Comparison with Molecular-Like Subtyping by Tumor Grade/Immunohistochemistry and Influence on Oncologist’s Decision on Systemic Therapy in a Real-World Setting

In intermediate risk hormone receptor (HR) positive, HER2 negative breast cancer (BC), the decision regarding adjuvant chemotherapy might be facilitated by multigene expression tests. In all, 142 intermediate risk BCs were investigated using the PAM50-based multigene expression test Prosigna® in a prospective multicentric study. In 119/142 cases, Prosigna® molecular subtyping was compared with local and two central (C1 and C6) molecular-like subtypes relying on both immunohistochemistry (IHC; HRs, HER2, Ki-67) and IHC + tumor grade (IHC+G) subtyping. According to local IHC, 35.4% were Luminal A-like and 64.6% Luminal B-like subtypes (local IHC+G subtype: 31.9% Luminal A-like; 68.1% Luminal B-like). In contrast to local and C1 subtyping, C6 classified >2/3 of cases as Luminal A-like. Pairwise agreement between Prosigna® subtyping and molecular-like subtypes was fair to moderate depending on molecular-like subtyping method and center. The best agreement was observed between Prosigna® (53.8% Luminal A; 44.5% Luminal B) and C1 surrogate subtyping (Cohen’s kappa = 0.455). Adjuvant chemotherapy was suggested to 44.2% and 88.6% of Prosigna® Luminal A and Luminal B cases, respectively. Out of all Luminal A-like cases (locally IHC/IHC+G subtyping), adjuvant chemotherapy was recommended if Prosigna® testing classified as Prosigna® Luminal A at high / intermediate risk or upgraded to Prosigna® Luminal B.     

Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.     

Statistical evaluation of dye desorption – mixed two- and three-level design and kinetic modeling

Abstract

Biosorption has been shown in the literature to be effective in the removal of dye from aqueous solution. To be fully useful, a desorption process is necessary, which has a direct impact on the process costs. The aim of this work was to evaluate the desorption of the azo dye Acid Yellow 23 adsorbed in a biosorbent obtained from Bombyx mori cocoons. Temperature and pH media were evaluated through a mixed two- and three-level design, using NaOH as desorbing agent. Kinetic desorption was also obtained at the optimized condition. The statistical evaluation of the experimental design showed that the pH has almost two times more influence on the dye desorption than the temperature, with only the linear parameters being statistically significant. Among four kinetic desorption models adjusted to the experimental data, the proposed n-order model was statistically determined as the best representation of the experimental data.     

Cold tolerance of Tineola bisselliella (Lepidoptera: Tineidae) eggs at slow cooling rate

Eggs of T. bisselliella were exposed to sub-zero temperatures at a cooling rate of 2°C/h to a minimum of −20°C. Observed mortality was closely approximated by predictions based on an adapted fixed temperature model. The eggs showed no acclimation during cooling. In combination with thermal conductivity models the mortality model provides a simple method to predict exposure times required to reach the desired level of mortality in the cold disinfestation treatment of a commodity or item. With large items, minimum dimension 50 cm, it is predicted that disinfestation will be achieved before the centre has reached −20°C.     

Ceramic-based chemical sensors, probes and field-tests in automobile engines

The monitoring and control of combustion-related emissions is a top priority in many industries. The major methods used to detect combustion gases fall short of practical applications for in-situ measurements in industrial environments involving high temperature and chemical contaminants. The real challenge is not only to develop highly sensitive and selective sensors, but to maintain long-term stability in such aggressive environments. This article presents an overview of a multidisciplinary research effort in ceramic-based chemical sensors, highlighting opportunities as well as challenges. The group of sensors (CO, NO _x , O₂, and CO₂) selected for this article can, in general, be used to determine the state of combustion in a wide variety of applications. Fabrication of sensor probes and their field-test results in automobile engines are also presented.     

Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer

PURPOSE: Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS: In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS: The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION: Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.     

Oxidative coupling of methane in a mixed-conducting perovskite membrane reactor

Ionic-electronic mixed-conducting perovskite-type oxide La_0.6Sr_0.4Co_0.8Fe_0.2O₃ was applied as a dense membrane for oxygen supply in a reactor for methane coupling. The oxygen permeation properties were studied in the p_O2-range of 10⁻³−1 bar at 1073–1273 K, using helium as a sweeping gas at the permeate side of the membrane. The oxygen semi-permeability has a value close to 1 mmol m⁻² s⁻¹ at 1173 K with a corresponding activation energy of 130–140 kJ/mol. The oxygen flux is limited by a surface process at the permeate side of the membrane. It was found that the oxygen flux is only slightly enhanced if methane is admixed with helium. Methane is converted to ethane and ethene with selectivities up to 70%, albeit that conversions are low, typically 1–3% at 1073–1173 K. When oxygen was admixed with methane rather than supplied through the membrane, selectivities obtained were found to be in the range 30–35%. Segregation of strontium was found at both sides of the membrane, being seriously affected by the presence of an oxygen pressure gradient across it. The importance of a surface limited oxygen flux for application of perovskite membranes for methane coupling is emphasized.     

Hollow glass microsphere composites: preparation and properties

Composites consisting of bonded hollow glass microspheres are promising for constructions in which materials are needed that combine a high Young's modulus with a low density. The elastic properties of ideally bonded hollow glass microsphere composites are predicted theoretically. Heat-treated castings of quartz glass microspheres approach the theoretical Young's modulus from below. The best result achieved was a Young's modulus of about 1 GPa with a strength of about 0.8 MPa at a density of about 180 kg m^–3. This was obtained with a casting of quartz glass microspheres, bonded with mono-aluminium phosphate. Composites made by pressing of appropriate microsphere/ binder mixtures, followed by heating, had a density that was lower than for castings but had a Young's modulus far below the theoretical value.     

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Topoisomerase I inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase I inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase I inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase I inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and GI147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.