The impact of polymorphic variations in the 5p15, 6p12, 6p21 and 15q25 loci on the risk and prognosis of Portuguese patients with non-small cell lung cancer

Polymorphic variants in the 5p15, 6p12, 6p21, and 15q25 loci were demonstrated to potentially contribute to lung cancer carcinogenesis. Therefore, this study was performed to assess the role of those variants in non-small cell lung cancer (NSCLC) risk and prognosis in a Portuguese population. MATERIALS AND METHODS: Blood from patients with NSCLC was prospectively collected. To perform an association study, DNA from these patients and healthy controls were genotyped for a panel of 19 SNPs using a Sequenom® MassARRAY platform. Kaplan-Meier curves were used to assess the overall survival (OS) and progression-free survival (PFS). RESULTS: One hundred and forty-four patients with NSCLC were successfully consecutively genotyped for the 19 SNPs. One SNP was associated with NSCLC risk: rs9295740 G/A. Two SNPs were associated with non-squamous histology: rs3024994 (VEGF intron 2) T/C and rs401681 C/T. Three SNPs were associated with response rate: rs3025035 (VEGF intron 7) C/T, rs833061 (VEGF -460) C/T and rs9295740 G/A. One SNP demonstrated an influence on PFS: rs401681 C/T at 5p15, p?=?0.021. Four SNPs demonstrated an influence on OS: rs2010963 (VEGF +405 G/C), p?=?0.042; rs3025010 (VEGF intron 5 C/T), p?=?0.047; rs401681 C/T at 5p15, p?=?0.046; and rs31489 C/A at 5p15, p?=?0.029. CONCLUSIONS: Our study suggests that SNPs in the 6p12, 6p21, and 5p15 loci may serve as risk, predictive and prognostic NSCLC biomarkers. In the future, SNPs identified in the genomes of patients may improve NSCLC screening strategies and therapeutic management as well.This project was supported by Programa Doutoral em Medicina e Oncologia Molecular, University of Porto, Porto, Portugal and University of Minho, Braga, Portugal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Early vs. deferred catheter ablation of ventricular tachycardia in patients of ischaemic substrate: systematic review and meta-analysis of clinical outcomes

Aims: Ventricular tachycardia (VT) ablation has been shown to reduce the recurrence of VT episodes, but the timing of performing VT ablation (early; at the time of implantable cardioverter defibrillator implantation) or (deferred: after the patient has received ICD shocks) remains controversial. The objective is to conduct a systematic review and meta-analysis of published data from randomized controlled trials (RCTs) in patients with ischaemic cardiomyopathy (ICM) with the aim of comparing outcome of VT ablation stratified by procedural timing. Methods and results: We conducted a meta-analysis of seven landmark RCTs which included patients with ICM who were either at a high risk of VT or experienced VT/ICD shocks. The primary outcome of VT recurrence was compared according to the timing of performing VT ablation (early vs. deferred). In addition, we also compared the secondary outcome of cardiac mortality. Following a comprehensive search strategy, a total of seven RCTs were included within the final analysis. Based on a pooled analysis, early VT ablation was associated with a significant reduction in the primary outcome [pooled odds ratio (OR) of 0.72, 95% confidence interval (CI): 0.55–0.95, P 30% vs. those with LVEF 30% amongst this ICM cohort

Evaluation of fast atmospheric dispersion models in a regular street network

The need to balance computational speed and simulation accuracy is a key challenge in designing atmospheric dispersion models that can be used in scenarios where near real-time hazard predictions are needed. This challenge is aggravated in cities, where models need to have some degree of building-awareness, alongside the ability to capture effects of dominant urban flow processes. We use a combination of high-resolution large-eddy simulation (LES) and wind-tunnel data of flow and dispersion in an idealised, equal-height urban canopy to highlight important dispersion processes and evaluate how these are reproduced by representatives of the most prevalent modelling approaches: (i) a Gaussian plume model, (ii) a Lagrangian stochastic model and (iii) street-network dispersion models. Concentration data from the LES, validated against the wind-tunnel data, were averaged over the volumes of streets in order to provide a high-fidelity reference suitable for evaluating the different models on the same footing. For the particular combination of forcing wind direction and source location studied here, the strongest deviations from the LES reference were associated with mean over-predictions of concentrations by approximately a factor of 2 and with a relative scatter larger than a factor of 4 of the mean, corresponding to cases where the mean plume centreline also deviated significantly from the LES. This was linked to low accuracy of the underlying flow models/parameters that resulted in a misrepresentation of pollutant channelling along streets and of the uneven plume branching observed in intersections. The agreement of model predictions with the LES (which explicitly resolves the turbulent flow and dispersion processes) greatly improved by increasing the accuracy of building-induced modifications of the driving flow field. When provided with a limited set of representative velocity parameters, the comparatively simple street-network models performed equally well or better compared to the Lagrangian model run on full 3D wind fields. The study showed that street-network models capture the dominant building-induced dispersion processes in the canopy layer through parametrisations of horizontal advection and vertical exchange processes at scales of practical interest. At the same time, computational costs and computing times associated with the network approach are ideally suited for emergency-response applications

Amplification of Microsatellites in the Persian Sturgeon (Acipenser Persicus)

Persian sturgeon (Acipenser persicus) is a benthic species occurring primarily on sandy bottoms in the mid and southern Caspian Sea, especially along the shores of Iran (Berg, 1948; Holcik, 1989). The Persian sturgeon in the Caspian Sea is anadromous, with at least eighteen groups that segregate spatially and temporally for spawning. These populations are supported by some spawners, each of which considered to be of two seasonal races and divided into two or four biological groups (Perevaryukha, 2001)

First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01

PURPOSE: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics. RESULTS: Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression. CONCLUSION: Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing

A Randomized Phase II Study to Assess the Efficacy of Pemetrexed or Sunitinib or Pemetrexed Plus Sunitinib in the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer

Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) improves survival modestly but new strategies are needed. This trial was designed to evaluate an antivascular endothelial growth factor strategy with or without standard chemotherapy in previously treated NSCLC

A Randomized Phase II Study to Assess the Efficacy of Pemetrexed or Sunitinib or Pemetrexed Plus Sunitinib in the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer

Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) improves survival modestly but new strategies are needed. This trial was designed to evaluate an antivascular endothelial growth factor strategy with or without standard chemotherapy in previously treated NSCLC