Peripheral T-cell lymphoma (PTCL) is comprised of a rare heterogeneous group of diseases with diverse clinical presentations; however outcomes associated with conventional chemotherapy are generally poor in the majority of patients. Newer approaches, which include dose-intensification and agents with novel mechanisms of action, are needed to improve outcomes in this group of patients. In this review we examine the results of two recent large Phase II trials with romidepsin, a histone deacetylase inhibitor which shows considerable activity and good tolerability in patients with T-cell lymphoma. These initial results observed with single-agent romidepsin provide a foundation for exploring combination strategies and demonstrates proof-of-principle that other such drugs with similar mechanisms of action may be effective in T-cell lymphoma.
In this study, a simple and rapid multi-residue screening method for the quantification and confirmation of 100 multi-class veterinary drugs in milk powder by the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method combined with liquid chromatography coupled to quadrupole time-of-flight mass spectrometry was developed. The veterinary drugs investigated belonged to several families such as macrolides, sulfonamides, quinolones, tetracyclines, nitroimidazoles, benzimidazoles, β-agonists, hormones, and tranquilizers. The samples were extracted using a modified QuEChERS procedure: (i) dissolved in a solution of Na2EDTA–McIlvaine buffer (0.1 M, pH 4), (ii) extracted with 5% acetic acid in acetonitrile, and (iii) purified using a C18 sorbent. The linearity, sensitivity, accuracy, repeatability, and reproducibility of the method were fully validated. The average recoveries for the majority of analytes (92.9%) ranged from 70 to 120% at four concentration levels, while the repeatability and reproducibility ranged from 1.1 to 20.1%. A coefficient of correlation (γ2) of 0.995 or above was obtained for all the compounds. The range of the limit of quantification for these compounds in the milk powder was from 0.1 to 25 μg kg−1. More than 93.0% of the analytes were detected when present at 10 μg kg−1 or less in the milk powder samples. For the screening method, the data of the precursor and product ions of the target analytes were simultaneously acquired under the All Ions MS/MS mode in a single run. A homemade library including the elemental composition, retention time, and full-scan product ions was utilized for the confirmation and identification of the target compounds. The applicability of the screening method was verified by applying to real milk powder samples, and certain veterinary drugs were detected in some cases.
Purpose of review Prostate-specific membrane antigen (PSMA) theranostics offers a new approach for a personalized and targeted treatment for metastatic prostate cancer. Lutetium-177-labelled PSMA-ligands (177Lu-PSMA) is a radionuclide therapy that is directed to PSMA expressing prostate cancer. Clinical experience with 177Lu-PSMA in men with advanced prostate cancer is growing. The purpose of this review is to outline the mechanism of action of this therapy, summarize recent efficacy and toxicity data and highlight future direction and challenges in establishing 177Lu-PSMA treatment as part of routine clinical practice. Recent findings The first reports on safety and efficacy of 177Lu-PSMA have been retrospective series of men with advanced prostate cancer who previously failed conventional therapies and received 177Lu-PSMA on compassionate basis. These studies highlight promising efficacy, favourable toxicity profile and quality of life improvements. Limitation stem from the retroospective nature of these data with short follow-up. Summary Several studies suggest that radionuclide therapy with 177Lu-PSMA has high activity and is well tolerated. Crucial to establishing this treatment in routine clinical management will be the generation of high-level evidence from prospective trials that can confirm the encouraging patient outcomes reported to date.
In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca 2+ elevation in astrocytes, by photolysis of caged Ca 2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca 2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca 2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca 2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca 2+ -dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.
Modular construction is increasingly adopted for mid to high-rise buildings due to its cost, speed and sustainability benefits, making fire safety a critical concern. However, research on composite modular structures under fire remains limited. This study investigates the fire-induced structural performance of a composite modular building with concrete-filled steel tubular (CFST) columns. Validation was conducted at both the component and system levels. A full building model was developed and analysed using SAFIR, a finite element-based software for thermal-structural analysis. A parametric analysis was then performed to explore the effects of fire curves, fire locations, multi-compartment fire spread and vertical spread to the upper module’s floor beams. Results show that the modular building exhibited good overall fire resistance, primarily due to the presence of CFST columns and system redundancy. Corner fires trigger earlier failure due to reduced restraint, while lower-floor fire causes earlier failure due to higher loads. Multi-compartment and vertical fire spread increase vulnerability by raising force demands on fire-exposed and adjacent members. The findings underscore the need for system-level modelling, as isolated analyses miss complex redistribution and failure mechanisms. • Fire behaviour of a composite modular building is numerically investigated. • Validation is performed at both component and system levels. • Good overall fire resistance is achieved due to CFST columns and redundancy. • Corner and lower-floor fires cause earlier failure due to restraint and loads. • Multi-compartment fire spread significantly increases structural vulnerability.
